Pesticidal compositions

ABSTRACT

The present invention concerns novel heteroaryl-N-aryl carbamates and their use in pest control, as insecticides and acaricides This invention also includes preparation of the pesticide compositions containing the compounds, and methods of controlling insects using the compounds.

This application claims the benefit of U.S. Provisional Application Ser.No. 61/232,142 filed on 7 Aug. 2009. The invention disclosed in thisdocument is related to the field of pesticides and their use incontrolling pests.

FIELD OF THE INVENTION Background of the Invention

Pests cause millions of human deaths around the world each year.Furthermore, there are more than ten thousand species of pests thatcause losses in agriculture. These agricultural losses amount tobillions of U.S. dollars each year. Termites cause damage to variousstructures such as homes. These termite damage losses amount to billionsof U.S. dollars each year. As a final note, many stored food pests eatand adulterate stored food. These stored food losses amount to billionsof U.S. dollars each year, but more importantly, deprive people ofneeded food.

There is an acute need for new pesticides. Insects are developingresistance to pesticides in current use. Hundreds of insect species areresistant to one or more pesticides. The development of resistance tosome of the older pesticides, such as DDT, the carbamates, and theorganophosphates, is well known. But resistance has even developed tosome of the newer pesticides. Therefore, a need exists for newpesticides and particularly for pesticides that have new modes ofaction.

SUBSTITUENTS Non-Exhaustive List

The examples given for the substituents are (except for halo)non-exhaustive and must not be construed as limiting the inventiondisclosed in this document.

“alkenyl” means an acyclic, unsaturated (at least one carbon-carbondouble bond), branched or unbranched, substituent consisting of carbonand hydrogen, for example, vinyl, allyl, butenyl, pentenyl, hexenyl,heptenyl, octenyl, nonenyl, and decenyl.

“alkenyloxy” means an alkenyl further consisting of a carbon-oxygensingle bond, for example, allyloxy, butenyloxy, pentenyloxy, hexenyloxy,heptenyloxy, octenyloxy, nonenyloxy, and decenyloxy.

“alkoxy” means an alkyl further consisting of a carbon-oxygen singlebond, for example, methoxy, ethoxy, propoxy, isopropoxy, 1-butoxy,2-butoxy, isobutoxy, tert-butoxy, pentoxy, 2-methylbutoxy,1,1-dimethylpropoxy, hexoxy, heptoxy, octoxy, nonoxy, and decoxy.

“alkyl” means an acyclic, saturated, branched or unbranched, substituentconsisting of carbon and hydrogen, for example, methyl, ethyl, propyl,isopropyl, 1-butyl, 2-butyl, isobutyl, tert-butyl, pentyl,2-methylbutyl, 1,1-dimethylpropyl, hexyl, heptyl, octyl, nonyl, anddecyl.

“alkynyl” means an acyclic, unsaturated (at least one carbon-carbontriple bond, and any double bonds), branched or unbranched, substituentconsisting of carbon and hydrogen, for example, ethynyl, propargyl,butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, and decynyl.

“alkynyloxy” means an alkynyl further consisting of a carbon-oxygensingle bond, for example, pentynyloxy, hexynyloxy, heptynyloxy,octynyloxy, nonynyloxy, and decynyloxy.

“aryl” means a cyclic, aromatic substituent consisting of hydrogen andcarbon, for example, phenyl, naphthyl, and biphenyl.

“cycloalkenyl” means a monocyclic or polycyclic, unsaturated (at leastone carbon-carbon double bond) substituent consisting of carbon andhydrogen, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl, cyclodecenyl, norbornenyl,bicyclo[2.2.2]octenyl, tetrahydronaphthyl, hexahydronaphthyl, andoctahydronaphthyl.

“cycloalkenyloxy” means a cycloalkenyl further consisting of acarbon-oxygen single bond, for example, cyclobutenyloxy,cyclopentenyloxy, cyclohexenyloxy, cycloheptenyloxy, cyclooctenyloxy,cyclodecenyloxy, norbornenyloxy, and bicyclo[2.2.2]octenyloxy.

“cycloalkyl” means a monocyclic or polycyclic, saturated substituentconsisting of carbon and hydrogen, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, norbornyl,bicyclo[2.2.2]octyl, and decahydronaphthyl.

“cycloalkoxy” means a cycloalkyl further consisting of a carbon-oxygensingle bond, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, cyclodecyloxy,norbornyloxy, and bicyclo[2.2.2]octyloxy.

“halo” means fluoro, chloro, bromo, and iodo.

“haloalkyl” means an alkyl further consisting of, from one to themaximum possible number of, identical or different, halos, for example,fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl,2-fluoroethyl, 2,2,2-trifluoroethyl, chloromethyl, trichloromethyl, and1,1,2,2-tetrafluoroethyl.

“heterocyclyl” means a cyclic substituent that may be fully saturated,partially unsaturated, or fully unsaturated, where the cyclic structurecontains at least one carbon and at least one heteroatom, where saidheteroatom is nitrogen, sulfur, or oxygen, for example, benzofuranyl,benzoisothiazolyl, benzoisoxazolyl, benzoxazolyl, benzothienyl,benzothiazolyl cinnolinyl, furanyl, indazolyl, indolyl, imidazolyl,isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, 1,3,4-oxadiazolyl,oxazolinyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl,quinoxalinyl, 1,2,3,4-tetrazolyl, thiazolinyl, thiazolyl, thienyl,1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, and1,2,4-triazolyl.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention have the following formula:

wherein:

(a) Ar₁ is

-   -   (1) furanyl, phenyl, pyridazinyl, pyridyl, pyrimidinyl, thienyl,        or    -   (2) substituted furanyl, substituted phenyl, substituted        pyridazinyl, substituted pyridyl, substituted pyrimidinyl, or        substituted thienyl,

wherein said substituted furanyl, substituted phenyl, substitutedpyridazinyl, substituted pyridyl, substituted pyrimidinyl, andsubstituted thienyl, have one or more substituents independentlyselected from H, F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆alkynyl, S(═O)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)H, C(═O)NR_(x)R_(y), (C₁-C₆alkyl)NR_(x)R_(y), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆haloalkyl), C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆ cycloalkyl),C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl), C(═O)O(C₂-C₆ alkenyl),(C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆ alkyl), C(═O)(C₁-C₆alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, phenoxy, substituted phenyl andsubstituted phenoxy

-   -   wherein such substituted phenyl and substituted phenoxy have one        or more substituents independently selected from H, F, Cl, Br,        I, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl,        C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆ halocycloalkoxy,        C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆        alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)H, C(═O)NR_(x)R_(y), (C₁-C₆        alkyl)NR_(x)R_(y), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl),        C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆        cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl),        C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆        alkyl)S(C₁-C₆ alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆        alkyl)phenyl, and phenoxy;

(b) Het is a 5 or 6 membered, saturated or unsaturated, heterocyclicring, containing one or more heteroatoms independently selected fromnitrogen, sulfur, or oxygen, and where Ar₁ and Ar₂ are not ortho to eachother (but may be meta or para, such as, for a five membered ring theyare 1,3 and for a 6 membered ring they are either 1,3 or 1,4), and wheresaid heterocyclic ring may also be substituted with one or moresubstituents independently selected from H, F, Cl, Br, I, CN, NO₂, oxo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl,C₃-C₆ cycloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆ alkyl),S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆ haloalkyl),C(═O)H, C(═O)NR_(x)R_(y), (C₁-C₆ alkyl)NR_(x)R_(y), C(═O)(C₁-C₆ alkyl),C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl),C(═O)(C₃-C₆ cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl),C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, phenoxy,substituted phenyl and substituted phenoxy

-   -   wherein such substituted phenyl and substituted phenoxy have one        or more substituents independently selected from H, F, Cl, Br,        I, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl,        C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆ halocycloalkoxy,        C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆        alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)H, C(═O)NR_(x)R_(y), (C₁-C₆        alkyl)NR_(x)R_(y), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl),        C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆        cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl),        C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆        alkyl)S(C₁-C₆ alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆ alkyl),        phenyl, and phenoxy;

(c) Ar₂ is

-   -   (1) furanyl, phenyl, pyridazinyl, pyridyl, pyrimidinyl, thienyl,        or    -   (2) substituted furanyl, substituted phenyl, substituted        pyridazinyl, substituted pyridyl, substituted pyrimidinyl, or        substituted thienyl,

wherein said substituted furanyl, substituted phenyl, substitutedpyridazinyl, substituted pyridyl, substituted pyrimidinyl, andsubstituted thienyl, have one or more substituents independentlyselected from H, F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆alkynyl, S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)H, C(═O)NR_(x)R_(y), (C₁-C₆alkyl)NR_(x)R_(y), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆haloalkyl), C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆ cycloalkyl),C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl), C(═O)O(C₂-C₆ alkenyl),(C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆ alkyl), C(═O)(C₁-C₆alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, phenoxy, substituted phenyl andsubstituted phenoxy (wherein such substituted phenyl and substitutedphenoxy have one or more substituents independently selected from H, F,Cl, Br, I, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl,C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆alkyl), S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆haloalkyl), C(═O)H, C(═O)NR_(x)R_(y), (C₁-C₆ alkyl)NR_(x)R_(y),C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆ haloalkyl),C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆ cycloalkyl), C(═O)O(C₃-C₆cycloalkyl), C(═O)(C₁-C₆ haloalkyl), C(═O)(C₂-C₆ alkenyl), C(═O)O(C₂-C₆alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆ alkyl),C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, and phenoxy;

(d) X₁ is O or S;

(e) X₂ is O or S;

(f) R4 is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆ alkyl),S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆ haloalkyl),C(═O)H, C(═O)NR_(x)R_(y), (C₁-C₆ alkyl)NR_(x)R_(y), C(═O)(C₁-C₆ alkyl),C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl),C(═O)(C₃-C₆ cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl),C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, phenoxy,

-   -   wherein each alkyl, haloalkyl, cycloalkyl, halocycloalkyl,        cycloalkoxy, halocycloalkoxy, alkoxy, haloalkoxy, alkenyl,        alkynyl, phenyl, and phenoxy are optionally substituted with one        or more substituents independently selected from F, Cl, Br, I,        CN, NO₂, oxo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁C₃-C₆ cycloalkyl,        C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆ halocycloalkoxy,        C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆        alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)H, C(═O)NR_(x)R_(y), (C₁-C₆        alkyl)NR_(x)R_(y), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl),        C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆        cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl),        C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆        alkyl)S(C₁-C₆ alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆ alkyl),        phenyl, and phenoxy;

(g) n=0, 1, or 2;

(h) R_(x) and R_(y) are independently selected from H, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, C₃-C₆cycloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,C₂-C₆ alkenyl, C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆haloalkyl), OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)H,C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆ haloalkyl),C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆ cycloalkyl), C(═O)O(C₃-C₆cycloalkyl), C(═O)(C₂-C₆ alkenyl), C(═O)O(C₂-C₆ alkenyl), (C₁-C₆alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆ alkyl), C(═O)(C₁-C₆alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, and phenoxy; and

(i) R1, R2, and R3 are independently selected from H, F, Cl, Br, I, CN,NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆halocycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C(═O)H, C(═O)NR_(x)R_(y),(C₁-C₆ alkyl)NR_(x)R_(y), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl),(C₁-C₆ alkyl)O(C₁-C₆ alkyl)O(C₁-C₆ alkyl), C(═O)(C₁-C₆ haloalkyl),C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆ cycloalkyl), C(═O)O(C₃-C₆cycloalkyl), C(═O)(C₂-C₆ alkenyl), C(═O)O(C₂-C₆ alkenyl), (C₁-C₆alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆ alkyl), C(═O)(C₁-C₆alkyl)C(═O)O(C₁-C₆ alkyl), C(═O)phenyl, phenyl, C₁-C₆ alkylphenyl,C(═O)phenoxy, phenoxy, C₁-C₆ alkylphenoxy, C(═O)Het-1, Het-1, or C₁-C₆alkylHet-1,

wherein Het-1 is a 5- or 6-membered, saturated or unsaturated,heterocyclic ring, containing one or more heteroatoms independentlyselected from nitrogen, sulfur or oxygen, and

wherein each alkyl, haloalkyl, cycloalkyl, halocycloalkyl, cycloalkoxy,halocycloalkoxy, alkoxy, haloalkoxy, alkenyl, alkynyl, phenyl, phenoxy,and Het-1, are optionally substituted with one or more substituentsindependently selected from F, Cl, Br, I, CN, NO₂, oxo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, C₃-C₆cycloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,C₂-C₆ alkenyl, C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆haloalkyl), OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)H,C(═O)NR_(x)R_(y), (C₁-C₆ alkyl)NR_(x)R_(y), (C₁-C₆ alkenyl)NR_(x)R_(y),(C₁-C₆ alkynyl)NR_(x)R_(y), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl),C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl),C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, phenoxy, andHet-1,

wherein R1 and R2 together can optionally form a 3- to 12-memberedsaturated or unsaturated cyclic group which may contain one or moreheteroatoms selected from nitrogen, sulfur, and oxygen (with the provisothat there is preferably not a C₁—O— bond in such cyclic group) whereinsaid cyclic group may have one or more substituents independentlyselected from F, Cl, Br, I, CN, NO₂, oxo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆alkynyl, S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)H, C(═O)NR_(x)R_(y), (C₁-C₆alkyl)NR_(x)R_(y), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆haloalkyl), C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆ cycloalkyl),C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl), C(═O)O(C₂-C₆ alkenyl),(C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆ alkyl), C(═O)(C₁-C₆alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, phenoxy, and Het-1.

In another embodiment Ar₁ is a substituted phenyl wherein saidsubstituted phenyl, has one or more substituents independently selectedfrom C₁-C₆ haloalkyl and C₁-C₆ haloalkoxy.

In another embodiment Het is a triazolyl.

In another embodiment Ar₂ is a phenyl.

In another embodiment R4 is H or C₁-C₆ alkyl.

In another embodiment R1, R2, and R3 are independently selected from H,CN, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C(═O)O(C₁-C₆ alkyl), phenyl, and Het-1.

In another embodiment R1, R2, and R3 are independently selected fromC₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C(═O)O(C₁-C₆ alkyl), phenyl, and Het-1. are substituted withone or more substituents independently selected from F, Cl, Br, I, CN,NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, S(═O)_(n)(C₁-C₆ alkyl),(C₁-C₆ alkyl)NR_(x)R_(y), (C₁-C₆ alkenyl)NR_(x)R_(y), (C₁-C₆alkynyl)NR_(x)R_(y), C(═O)O(C₁-C₆ alkyl), and phenyl.

In another embodiment when R1, R2, and R3 are Het-1 they areindependently selected from pyrimidinyl, pyridyl, quinolinyl, thiazolyl,thienyl, furanyl, isoxazolyl, each of which may be optionallysubstituted.

In another embodiment Het and Het-1 when they have a ring nitrogeninclude (N⁺—O⁻) group.

While these embodiments have been expressed, other embodiments andcombinations of these expressed embodiments and other embodiments arepossible.

Preparation of Triaryl-Intermediates

Compounds of this invention are prepared by linking the X₂(C₁)R1R2R3 toa triaryl intermediate, Ar₁-Het-Ar₂, by means of a carbamate orthiocarbamate linkage N₁(C═X₁) (defined above). A wide variety oftriaryl precursors can be used to prepare compounds of this invention,provided that they contain a suitable functional group on Ar₂. Suitablefunctional groups include an amino, or carboxylic acid group. Thesetriaryl-intermediates can be prepared by methods previously described inthe chemical literature. Several of these methods are described below.

Intermediates wherein ‘Het’ is a disubstituted pyridine, pyrimidine,pyrazine or pyridizine can be made by coupling of a halo- oralkylthio-substituted pyridine, pyrimidine or pyrazine with an arylboronic acid or borate ester, under Suzuki arylation conditions. See,for example, the following.

For pyridines: Couve-Bonnaire et al. Tetrahedron 2003, 59, 2793 andPuglisi et al. Eur. J. Org. Chem. 2003, 1552.

For pyrazines: Schultheiss and Bosch Heterocycles 2003, 60, 1891.

For pyrimidines: Qing et al. J. Fluorine Chem. 2003, 120, 21 and Ceideand Montalban Tetrahedron Lett. 2006, 47, 4415.

For 2,4-diaryl pyrimidines: Schomaker and Delia J. Org. Chem. 2001, 66,7125.

Thus, successive palladium-catalyzed arylations, using 4-formylphenylboronic acid and 4-trifluoromethoxyphenyl boronic acid, can generatevirtually any particular substitution pattern, as shown in the schemebelow:

Similarly, diaryl pyridines and pyrazines and other dihalogenatedheterocyclic aromatic compounds can be prepared from dihalogenatedpyridines and pyrazines and other dihalogenated heterocyclic aromaticcompounds using the same protocol:

The halo- or alkylthio-pyrimidine and pyridine precursors are eithercommercially available, or may be synthesized by routes described in theliterature (Rorig and Wagner U.S. Pat. No. 3,149,109, 1964; Kreutzbergerand Tesch Arzneim.-Forsch. 1978, 28, 235).

Compounds where ‘Het’ is a 1,3-diaryl-6-perfluoroalkyl pyrimidine can beprepared according to the following scheme. The 2-methylthio-substitutedpyrimidine was arylated under modified Suzuki conditions (Liebeskind andSrogl Org. Lett. 2002, 4, 979) to give 2-phenyl pyrimidines, which thenwere reduced to the corresponding anilines using, for example, apalladium on carbon (Pd/C) catalyst in EtOH under a hydrogen atmosphere.

Intermediate compounds wherein ‘Het’ is a 1,3-disusbstituted1,2,4-triazole can be prepared according to one of the followingschemes.

Route A: 1,3-Diaryl 1,2,4-triazoles were prepared from the corresponding—NH 3-aryl 1,2,4-triazoles by following a published route forN-arylation of imidazoles (Lin et al. J. Org. Chem. 1979, 44, 4160).Coupling of 1,2,4-triazoles to aryl halides was done under thermal or,preferably, microwave conditions (Antilla et al. J. Org. Chem. 2004, 69,5578).

Route B: Bromination of hydrazones followed by treatment of thebromohydrazone with tetrazole results in formation of the 1,3-diaryl1,2,4-triazole (Butler and Fitzgerald J. Chem. Soc., Perkin Trans. 11988, 1587).

Route C. 1,2,4-Triazole compounds in which the 5-position is furthersubstituted with an alkyl or substituted alkyl group can be preparedaccording to the following scheme (Paulvannan and Hale Tetrahedron 2000,56, 8071):

Compounds where ‘Het’ is an imidazole can be prepared according to oneof the following schemes:

Route A (Step 1: Lynch et al. J. Am. Chem. Soc. 1994, 116, 11030. Step2: Liu et al. J. Org. Chem. 2005, 70, 10135):

Route B. For halo-aryl groups that also contain an activating group suchas nitro or cyano, displacement of an aryl halide with an imidazole,using a base such as potassium carbonate in a polar aprotic solvent,such as N,N-dimethylformamide (DMF) or dimethyl sulfoxide (DMSO), can beaccomplished in the following manner (Bouchet et al. Tetrahedron 1979,35, 1331):

Route C: Following a procedure first described by Porretta et al.(Farmaco, Edizione Scientifica 1985, 40, 404), an N-phenacyl aniline istreated with potassium thiocyanate in acidic medium (HCl), and theresulting 2-mercapto imidazole is then converted into the desulfurizeddiaryl imidazole by treatment with nitric acid in acetic acid.

Route D. N-Arylation of 4-bromoimidazole under microwave irradiationconditions (Route A, Step 2) furnished the intermediate1-aryl-4-bromoimidazole, which was converted into triaryl-intermediatesby treatment with aryl boronic acids under palladium-catalyzedconditions.

Compounds where ‘Het’ is a 1,4-disubstituted 1,2,3-triazole can beprepared according to the following scheme (Feldman et al. Org. Lett.2004, 6, 3897):

Compounds where ‘Het’ is a 3,5-disubstituted 1,2,4-triazole can beprepared according to the following scheme (Yeung et al. TetrahedronLett. 2005, 46, 3429):

Compounds where ‘Het’ is a 1,3-disubstituted 1,2,4-triazolin-5-one canbe prepared according to the following scheme (Pirrung and Tepper J.Org. Chem. 1995, 60, 2461 and Lyga Synth. Commun. 1986, 16, 163). (DPPAis diphenyl phosphoryl azide):

Compounds where ‘Het’ is a 1,3-diaryl pyrazoline can be preparedaccording to the following scheme. The monohydrazone ofterephthalaldehyde is treated with N-chlorosuccinimide (NCS) in i-PrOH,and the resulting chlorohydrazone intermediate is treated directly withbase and a substituted olefin to generate the pyrazoline:

Compounds where ‘Het’ is a 3,5-disubstituted isoxazole can be preparedaccording to the following scheme:

Compounds where ‘Het’ is a 1,3-disubstituted pyrazole can be preparedaccording to the following scheme. Coupling of the pyrazole tohalogenated aromatics was accomplished using microwave conditionsdescribed by Liu et al., Route A, Step 2 above. (DMA is dimethylacetal.)

Compounds where ‘Het’ is a 2,4-disubstituted thiazole are prepared bycondensation of a thioamide to an α-halo acetophenone in a proticsolvent such as ethanol (for example, Potts and Marshall J. Org. Chem.1976, 41, 129).

Compounds where ‘Het’ is a 1,4-disubstituted 1,2,4-triazolin-5-one areprepared according to the following scheme (Henbach DE 2724819 A1, 1978with slight modification to two steps):

Compounds where ‘Het’ is a 2,4-disubstituted oxazoline are preparedstarting from the α-bromoacetophenone according to the following scheme(Periasamy et al. Synthesis 2003, 1965 and Liu et al. J. Am. Chem. Soc.2007, 129, 5834).

Compounds where ‘Het’ is a 2,5-disubstituted oxazoline are preparedaccording to the following scheme (Favretto et al. Tetrahedron Lett.2002, 43, 2581 and Liu et al. J. Am. Chem. Soc. 2007, 129, 5834):

Compounds where ‘Het’ is a 1,4-disubstituted piperazine are preparedaccording to the following scheme (Evans et al. Tetrahedron Lett. 1998,39, 2937):

Compounds where ‘Het’ is a 1,3-disubstituted pyrazoline are prepared byaddition of an aryl hydrazine to a β-dimethylamino propiophenone asshown in the following scheme, which is described in Linton et al.Tetrahedron Lett. 2007, 48, 1993, and Wheatley et al. J. Am. Chem. Soc.1954, 76, 4490. In addition to the pyrazoline, a minor amount ofbis-addition leads to the corresponding dimethylaminomethylpyrazoline.These materials can be separated chromatographically.

Compounds where ‘Het’ is a 3,5-disubstituted 1,2,4-triazine are preparedaccording to the following scheme (Reid et al. Bioorg. Med. Chem. Lett.2008, 18, 2455 and Saraswathi and Srinivasan Tetrahedron Lett. 1971,2315):

Compounds where ‘Het’ is a 2-ketopiperazine or 2,5-diketopiperazine areprepared as in the following scheme. The nitrophenyl glycine ester canbe acylated using chloroacetyl chloride, and the intermediateN-chloroacetylated glycine ester, upon treatment with an aniline,undergoes displacement and ring closure at from 120 to 180° C. to form adiketopiperazine. Alternatively, monoketo saturated or unsaturatedpiperazines can be formed from the acetal intermediate below, byhydrolysis and ring closure.

Preparation of (Thio)Carbamate-Linked Compounds

Carbamate- or thio-carbamate linked compounds can be prepared from thecorresponding aryl amines by conversion into either an isocyanate,isothiocyanate or p-nitrophenyl carbamate, followed by treatment withthe appropriate alcohol (ROH) and an organic or inorganic base in asuitable solvent such as tetrahydrofuran (THF), at temperatures between0 and 100° C. Alternatively, the carbamate can be formed from achloroformate, generated from the alcohol (ROH) by treatment withtriphosgene in the presence of a base such as pyridine, followed byreaction with an appropriate amine.

An isocyanate intermediate can be generated from the carboxylic acid bytreating with a source of azide such as diphenylphosphoryl azide (DPPA).The acyl azide then can be made to undergo a Curtius rearrangement byheating to 110° C. in toluene, and the resulting isocyanate treated withan appropriate alcohol and a base as described above to generate thecarbamate. The precursor carboxylic acids can be prepared via oxidationof an aldehyde, using conditions described in Example 18, via basichydrolysis of a nitrile (for example4-(1-(4-trifluoromethoxyphenyl)-1,2,4-triazol-3-yl)-benzonitrile asdescribed in Example 10), or via acidic hydrolysis of a nitrile usingany of a variety of conditions described in the literature.

Carbamates can also be prepared via nitrophenyl carbonates as shownbelow and demonstrated in McClure and Sieber Heteroat. Chem. 2000, 11,192. Reaction of a tertiary carbinol with potassium metal, followed byaddition of p-nitrophenyl chloroformate, provides the desiredp-nitrophenyl carbonate. Subsequent reaction of the carbonate with anamine in the presence of sodium carbonate in DMF affords the carbamate.

Alkynyl carbamates can be further functionalized by deprotonation with abase, such as n-butyl lithium, in a polar aprotic solvent, such as THF,followed by reaction with ethyl chloroformate to provide the substitutedalkyne.

Alkene-containing carbamates can be further functionalized viahydroboration-oxidation with borane-dimethyl sulfide complex, followedby treatment with sodium perborate tetrahydrate.

EXAMPLES

The examples are for illustration purposes and are not to be construedas limiting the invention disclosed in this document to only theembodiments disclosed in these examples.

Starting materials, reagents and solvents which were obtained fromcommercial sources were used without further purification. Anhydroussolvents were purchased as Sure/Seal™ from Aldrich and were used asreceived. Melting points were obtained on a Thomas Hoover Unimeltcapillary melting point apparatus or an OptiMelt Automated Melting PointSystem from Sanford Research Systems and are uncorrected.

Examples 1-55 illustrate the preparation of additional molecules usefulin making various embodiments of this invention.

Example 1 Preparation of4-[1-(4-trifluoromethoxyphenyl)-1H-pyrrol-3-yl]-benzaldehyde

Step 1. 1-(4-Trifluoromethoxyphenyl)-1H-pyrrole. The compound wasprepared according to Colotta et al. J. Med. Chem. 2006, 49, 6015. Asolution of 4-trifluoromethoxyphenyl amine (500 milligrams (mg), 2.82millimoles (mmol), 1.00 equivalent (eq)) and 2,5-diethoxytetrahydrofuran (452 mg, 2.82 mmol, 1.00 eq) in glacial acetic acid (20milliliters (mL)) was heated at 90° C. for 1 hour (h) before being driedonto silica gel. The residue was then slurried in refluxing hexane,filtered hot, and concentrated to dryness affording the desiredintermediate (519 mg, 81%).

Step 2. 3-Bromo-1-(4-trifluoromethoxyphenyl)-1H-pyrrole. The compoundwas prepared according to Bray et al. J. Org. Chem. 1990, 55, 6317. To asolution of 1-(4-trifluoromethoxyphenyl)-1H-pyrrole (519 mg, 2.29 mmol,1.00 eq) in THF (250 mL) at −78° C. was added a 0.05 M solution ofN-bromosuccinimide (NBS; 408 mg, 2.29 mmol, 1.00 eq) in THF over 45minutes (min). The vessel was slowly warmed to room temperature beforeconcentration to afford the crude bromopyrrole, which was shown toconsist of 55% desired intermediate by GC-MS. The material was used inthe subsequent reaction without further purification.

Step 3. 4-[1-(4-Trifluoromethoxyphenyl)-1H-pyrrol-3-yl]-benzaldehyde. Asuspension of crude 3-bromo-1-(4-trifluoromethoxyphenyl)-1H-pyrrole (356mg, 1.26 mmol, 1.00 eq), 4-formylphenylboronic acid (283 mg, 1.89 mmol,1.50 eq), bis(triphenylphosphine)palladium(II) dichloride (27 mg, 0.04mmol, 0.03 eq), 2 M Na₂CO₃ (aq) (1.26 mL, 2.52 mmol, 2.0 eq), and1,4-dioxane (5 mL) were heated at 150° C. in a microwave reaction vesselfor 45 min. The cooled solution was then diluted with EtOAc (20 mL),filtered over Celite®, concentrated to dryness, and purified viachromatography (2:2:1, hexane:EtOAc:acetone) to afford the desiredintermediate (79 mg, 21%).

Example 2 Preparation of4-[1-(4-trifluoromethoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl]-benzaldehyde

Step 1. 1-(4-Trifluoromethoxyphenyl)-pyrazolidin-3-one: The compound wasprepared according to Rees and Tsoi Chem. Commun. 2000, 415. Asuspension of (4-trifluoromethoxyphenyl)-hydrazine hydrochloride (300mg, 1.32 mmol, 1.00 eq), 3-chloropropionyl chloride (167 mg, 1.32 mmol,1.00 eq), and PS-DIEA (1.30 grams (g), 5.28 mmol, 4.00 eq) in THF (20mL) was stirred at ambient temperature for 12 h. The solution was thenfiltered, concentrated to dryness, and purified via chromatography(2:2:1, hexane:EtOAc:acetone) to afford the desired intermediate (120mg, 37%).

Step 2. 3-Chloro-1-(4-trifluoromethoxyphenyl)-4,5-dihydro-1H-pyrazole:The general procedure was taken from Wang et al. Tetrahedron Lett. 2005,46, 2631. To a solution of1-(4-trifluoromethoxyphenyl)-pyrazolidin-3-one (120 mg, 0.49 mmol, 1.00eq) in toluene (20 mL) was slowly added phosphoryl chloride (22.5 mg,1.47 mmol, 3.00 eq). The mixture was then heated at 80° C. for 1 hbefore cooling to room temperature and quenching with H₂O (10 mL). Thevessel was stirred under an atmosphere of nitrogen (N₂) for 8 h beforethe product was extracted into EtOAc (200 mL), dried (MgSO₄), andconcentrated under reduced pressure. GC-MS proved 88% formation of thedesired intermediate, which was used in subsequent reactions withoutfurther purification.

Step 3.4-[1-(4-Trifluoromethoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl]-benzaldehyde:A suspension of3-chloro-1-(4-trifluoromethoxyphenyl)-4,5-dihydro-1H-pyrazole (114 mg,0.43 mmol, 1.00 eq), 4-formylphenylboronic acid (97 mg, 0.65 mmol, 1.50eq), bis(triphenylphosphine)palladium(II) dichloride (10 mg, 0.01 mmol,0.03 eq), 2 M Na₂CO₃ (aq) (0.43 mL, 0.86 mmol, 2.0 eq), and 1,4-dioxane(5 mL) were heated at 150° C. in a microwave reaction vessel for 45 min.The cooled solution was then diluted with EtOAc (20 mL), filtered overCelite®, concentrated to dryness, and purified via chromatography(2:2:1, hexane:EtOAc:acetone) to afford the desired intermediate (50 mg,0.15 mmol, 31%).

Example 3 Preparation of4-[1(5-bromo-2-chlorophenyl)-1H-imidazol-4-yl]-benzonitrile

The compound was prepared according to Liu et al. J. Org. Chem. 2005,70, 10135. 4-(1H-Imidazol-4-yl)-benzonitrile (75 mg, 0.44 mmol; preparedfrom 4-(2-bromo-acetyl)-benzonitrile using the method of Lynch et al. J.Am. Chem. Soc. 1994, 116, 11030), 4-bromo-1-chloro-2-iodobenzene (169mg, 0.532 mmol), Cs₂CO₃ (577 mg, 1.77 mmol), CuI (3 mg, 0.013 mmol),8-hydroxyquinoline (2 mg, 0.013 mmol), and DMF/H₂O (2 mL; 10:1 solution)were combined in a 10 mL CEM Microwave reaction vessel fitted withmagnetic stir bar and subjected to microwave irradiation at 150° C. for30 min. The contents were then filtered and concentrated to drynessaffording intermediate5-bromo-2-chlorophenyl)-1H-imidazol-4-yl]-benzonitrile (68 mg, 43%).

Example 4 Preparation of4-[5-(4-propylphenyl)-isoxazol-3-yl]-benzonitrile

Step 1. 4-(Hydroxyiminomethyl)-benzonitrile. The compound was preparedaccording to Biasotti et al. Bioorg. Med. Chem. 2003, 11, 2247. Asuspension of 4-formylbenzonitrile (500 mg, 3.81 mmol, 1.00 eq),hydroxylamine hydrochloride (290 mg, 4.19 mmol, 1.10 eq), and sodiumacetate (1.56 g, 19.05 mmol, 5.00 eq) in MeOH (50 mL) was heated at 70°C. for 4 h before concentration to dryness. The residue was thenslurried in Et₂O, filtered, and concentrated to afford the desiredintermediate (496 mg, 3.39 mmol, 89%).

Step 2. 4-(Hydroxyimino-bromomethyl)-benzonitrile. The compound wasprepared according to Tanaka et al. Bull. Chem. Soc. Jpn. 1984, 57,2184. A 0.05 M solution of NBS (724 mg, 4.07 mmol, 1.20 eq) in CH₂Cl₂was added dropwise to a 0° C. solution of4-(hydroxyiminomethyl)-benzonitrile (496 mg, 3.39 mmol, 1.00 eq) inCH₂Cl₂ (50 mL). The solution was warmed to room temperature before beingvolumetrically partitioned between two different reaction vials. Eachvial was then concentrated and the crude residues were used withoutfurther purification.

Step 3. 4-[5-(4-Propylphenyl)-isoxazol-3-yl]-benzonitrile. A solution of4-(hydroxyimino-bromomethyl)-benzonitrile (381 mg, 1.70 mmol),triethylamine (0.71 mL, 5.10 mmol, 3.0 eq), and1-ethynyl-4-propylbenzene (1.23 g, 8.50 mmol, 5.0 eq) in toluene (20 mL)was heated at 100° C. for 1 h before concentration to dryness.Purification via normal phase chromatography afforded the desiredintermediate (108 mg, 22%).

Example 5 Preparation of4-{1-[4-(1-hydroxypropyl)-phenyl]-1H-pyrazol-3-yl}-benzonitrile

Step 1. 3-(4-Cyanophenyl)pyrazole. To a round bottom flask equipped withstir bar and reflux condenser were added p-cyanoacetophenone (5 g, 34.44mmol) and dimethylformamide dimethylacetal (DMF-DMA; 40 mL). The mixturewas stirred at reflux for 5 h before concentration under reducedpressure afforded the crude dimethylamino-acryloylbenzonitrileintermediate. The residue was then suspended in a minimal volume of EtOH(−20 mL), charged with hydrazine monohydrate (1.67 mL, 34.4 mmol), andheated at 80° C. for 30 min before concentration. The crude3-(4-cyanophenyl)pyrazole material (5.59 g, 33 mmol, 96%) which wasisolated was of sufficient purity for use in the subsequent reaction.

Step 2. 4-[1-(4-Propionyl-phenyl)-1H-pyrazol-3-yl]-benzonitrile.4-(1H-Pyrazol-3-yl)-benzonitrile (100 mg, 0.591 mmol),1-(4-bromophenyl)-propan-1-one (126 mg, 0.591 mmol), Cs₂CO₃ (770 mg,2.364 mmol), CuI (4 mg, 0.018 mmol), 8-hydroxyquinoline (3 mg, 0.018mmol), and DMF/H₂O (2 mL; 10:1 solution) were combined in a 10 mL CEMMicrowave reaction vessel fitted with magnetic stir bar and subjected tomicrowave irradiation at 150° C. for 30 min. The contents were thenfiltered and concentrated to dryness affording the nitrile (158 mg,0.508 mmol, 86%).

Example 6 Preparation of5-(4-formylphenyl)-2-(4-trifluoromethoxyphenyl)-3,4-dihydro-2H-pyrazole-3,4-dicarboxylicacid diethyl ester

Step 1. Preparation of4-[(4-trifluoromethoxyphenyl)-hydrazonomethyl]-benzaldehyde. Thecompound was prepared according to Paulvannan et al. Tetrahedron. 2000,56, 8071. To a stirred solution of benzene-1,4-dicarbaldehyde (1.50 g,11.2 mmol, 1.0 eq) in i-PrOH (250 mL) was added4-trifluoromethoxy)phenylhydrazine hydrochloride (2.55 g, 11.2 mmol, 1.0eq) portionwise over 5 min. The solution was stirred at ambienttemperature for 1 h before concentration to dryness and purification viachromatography (2:2:1 hexane:EtOAc:acetone) to afford the intermediate(2.48 g, 72%).

Step 2. Chlorohydrazone synthesis. The intermediate was preparedaccording to Lokanatha Rai and Hassner Synth. Commun. 1989, 19, 2799. Asolution of 4-[4(4-trifluoromethoxyphenyl)-hydrazonomethyl]-benzaldehyde(2.48 g, 8.05 mmol, 1.00 eq) and N-chlorosuccinimide (1.61 g, 12.08mmol, 1.5 eq) in i-PrOH (100 mL) was heated at 80° C. for 1 h. Thesolution was then cooled and volumetrically partitioned evenly betweensix different reaction vessels to each contain 1.34 mmol of theintermediate.

Step 3. Pyrazoline synthesis. The compounds were prepared according toPaulvannan et al. Tetrahedron 2000, 56, 8071. To each reaction vesselwere added triethylamine (0.56 mL, 4.02 mmol, 3.00 eq) and therespective acrylates (6.70 mmol, 5.00 eq). The reaction mixtures werethen heated at 70° C. for 90 min before concentration to dryness andpurification via chromatography (2:2:1 hexane:EtOAc:acetone).

Example 7 Preparation of4-{1-[4-(2,2,2-trifluoroethoxy)-phenyl]-1H-imidazol-4-yl}-benzonitrile

4-(2-Bromoacetyl)-benzonitrile (58 mg, 0.21 mmol) and4-(2,2,2-trifluoroethoxy)-phenylamine (50 mg, 0.21 mmol) were combinedin a 100 mL Erlenmeyer flask fitted with magnetic stir bar. The contentswere dissolved in EtOH (1 mL) and stirred at ambient temperature for 2h. The crude intermediate was then transferred to a 100 mL round bottomflask containing KSCN (21 mg, 0.21 mmol) and conc. HCl (18 μL, 0.21mmol). The vessel was heated at 80° C. for 1 h before its contents werepoured into 5 mL of a 1:1 H₂O/NH₄OH solution. The solution was allowedto stand for 24 h, and then the solid was filtered and washed with etherto afford the intermediate imidazolethiol (32 mg, 0.086 mmol, 33%). Anaqueous solution of HNO₃ (1.35 mL, 0.387 mmol) and KNO₃ (1 mg, 0.003mmol) was then added dropwise over 10 min to a suspension of theimidazolethiol in acetic acid (2 mL). After stirring for 2 h at ambienttemperature the solution was poured into crushed ice and neutralized(pH=7) with 0.1 N sodium hydroxide (NaOH, aq). The nitrile was isolatedby vacuum filtration and dried in a 45° C. vacuum oven for 12 h (23 mg,78%), mp 179° C.

Example 8 Preparation of4-[1-(4-propylphenyl)-1H-imidazol-4-yl]-benzonitrile

4-Propylaniline (2.70 g, 20 mmol) was added dropwise to a solution of4-cyanophenacyl bromide (2.20 g, 10 mmol) in DMF (5 mL). This solutionwas then added to hot (180° C.) formamide (20 mL) over 5 min, and thecombined solution was allowed to stir at 180° C. for 2 h. The cooledsolution was then poured onto ice (100 mL), and extracted with ether(2×75 mL). After drying and concentrating, the resulting dark oil waspurified by chromatography (3:1:2 hexanes:EtOAc:CH₂Cl₂). The firstproduct (510 mg) was identified as4-(5-propyl-1H-indol-3-yl)-benzonitrile, mp 140° C. The second fraction(275 mg) was identified as the desired imidazole: mp 133° C.; ¹H NMR(400 MHz, CDCl₃) δ 7.95 (d, J=6 Hz, 2H), 7.90 (s, 1H), 7.70 (d, J=6 Hz,2H), 7.68 (s, 1H), 7.38 (d, J=4 Hz, 2H), 7.31 (d, J=4 Hz, 2H), 2.69 (t,J=8.9 Hz, 2H), 1.68 (m, 2H), 0.98 (t, J=7.5 Hz, 3H); ESIMS m/z 288.1(M+H).

Example 9 Preparation of4-[1-(4-trifluoromethoxyphenyl)-1H-imidazol-4-yl]-benzonitrile

4-Trifluoromethoxyaniline (2.20 g, 12.4 mmol) was added dropwise to asolution of 4-cyanophenacyl bromide (1.50 g, 6.7 mmol) in DMF (5 mL).This solution was then added to hot (180° C.) formamide (20 mL) over 5min, and the combined solution was allowed to stir at 180° C. for 2 h.The cooled solution was then poured onto ice (100 mL), and extractedwith ether (2×75 mL). After drying and concentrating, the resultingsemi-solid was crystallized from MeOH/H₂O. A second recrystallizationfrom MeOH/H₂O removed traces of the formanilide impurity and furnishedpure product (200 mg): mp 155° C. Anal. Calcd. for C₁₇H₁₀F₃N₃O: C,62.01; H, 3.06; N, 12.76. Found: C. 61.53; H, 3.13; N, 12.55.

Example 10 Preparation of4-[1-(4-trifluoromethoxyphenyl)-1H-imidazol-4-yl]-benzoic acid

A solution of the nitrile (1.1 g, 3.3 mmol) in EtOH (5 mL) and water (2mL) was treated with NaOH (1 g, 20 mmol), and the solution was heated toreflux for 6 h. It was then cooled and made acidic with 1 N HCl, and theresulting white solid was filtered and air-dried to give the acid (1.1g) as a light grey solid: mp 230° C.; ¹H NMR (400 MHz, CDCl₃) δ 11.4 (s,1H), 7.90 (d, J=6.4 Hz, 2H), 7.89 (s, 1H), 7.80 (d, J=8.6 Hz, 2H), 7.63(d, J=1.3 Hz, 1H), 7.49 (d, J=9.3 Hz, 2H), 7.38 (d, J=8.9 Hz, 2H).

Example 11 Preparation of4-[4-(4-trifluoromethylphenyl)-1H-imidazol-1-yl]-benzonitrile

4-Trifluoromethylphenyl imidazole (4.0 g, 19 mmol), 4-fluorobenzonitrile(1.2 g, 8.5 mmol) and potassium carbonate (1.5 g, 10.9 mmol) werecombined in DMSO (15 mL) and heated at 100° C. for 6 h. The cooledsolution was then poured onto water (100 mL), and the resulting solidwas filtered and air-dried to give the imidazole nitrile (4.65 g) as awhite solid: mp 252° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.05 (s, 1H), 7.95(d, J=8 Hz, 2H), 7.85 (d, 2H), 7.72 (s, 1H), 7.72 (d, J=8 Hz, 2H), 7.62(d, J=8 Hz, 2H); ESIMS m/z 314.1 (M+H). Anal. Calcd. for C₁₆H₁₀F₃N₃O₂:C, 65.18; H, 3.22; N, 13.41. Found: C, 64.49; H, 3.23; N, 13.08.

Example 12 Preparation of4-bromo-1-(4-trifluoromethoxyphenyl)-1H-imidazole

A round bottom flask was charged with 4-bromoimidazole (1.15 g, 7.81mmol), CuI (0.07 g, 0.36 mmol), 8-hydroxyquinoline (0.05 g, 0.36 mmol),cesium carbonate (3.39 g, 10.4 mmol) and 4-trifluoromethoxyiodobenzene(1.50 g, 5.21 mmol). A 10:1 mixture of DMF (15 mL) and H₂O (1.5 mL) wasadded to the reaction mixture, and the solution was heated to 130° C.for 4 h. The reaction mixture was then diluted with EtOAc and washedsequentially with water, ammonium chloride (saturated), water and sodiumbicarbonate. The organics were dried over MgSO₄, filtered and purifiedon a reverse phase column to give the imidazole (820 mg) as a whitesolid: mp 139-141° C.; ESIMS m/z 308.0 (M+H).

Example 13 Preparation of4-methoxy-2-[1-(4-trifluoromethoxyphenyl)-1H-imidazol-4-yl]-benzaldehyde

4-Bromo-1-(4-trifluoromethoxyphenyl)-1H-imidazole (100 mg, 0.326 mmol),2-formyl-5-methoxyphenylboronic acid (73 mg, 0.41 mmol),bis(triphenylphosphine)palladium dichloride (2 mg, 0.003 mmol), sodiumbicarbonate (49 mg, 0.59 mmol) and 1:1 DME/H₂O (8:8 mL) were combinedand added to a microwave vessel. The reaction mixture was heated in themicrowave with stirring at 100° C. for 12 min. The microwave took 5 minto reach 100° C., then maintained at 100° C. for 12 min, and thencooled. TLC (1:1 EtOAc:cyclohexane) showed the presence of startingmaterials, thus the sample was heated to 100° C. for another 8 min. Uponcooling a precipitate formed; this was filtered and washed with water togive a grey solid (86 mg): ESIMS m/z 363.0 (M+H).

The following intermediate was also prepared using this procedure:

Example 14 Preparation of2-fluoro-4-[1-(4-trifluoromethoxyphenyl)-1H-imidazol-4-yl]-benzaldehyde

ESIMS m/z 351.0 (M+H).

Example 15 Preparation of4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-benzonitrile

Step 1. 4-(1H-[1,2,4]Triazol-3-yl)-benzonitrile. The general procedureoutlined by Lin et. al. (J. Org. Chem. 1979, 44, 4163) for preparationof 3-(4-nitrophenyl)-1H-[1,2,4]triazole was used. 4-Cyanobenzamide(21.63 g, 0.148 mol) was dissolved in DMF-DMA (100 mL) and was stirredat reflux under N₂ for 8 h. The mixture was concentrated to dryness andsuspended in AcOH (50 mL). The vessel was then charged with hydrazinemonohydrate (7.18 mL, 0.148 mmol) and stirred at reflux for 1 h beforeconcentration. The desired 4-(1H-[1,2,4]triazol-3-yl)-benzonitrile wasobtained in 98% purity by trituration with Et₂O followed by filtration(12.17 g, 0.072 mol, 48%).

Step 2.4-[1-(4-Trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-benzonitrile.The triazole (70 mg, 0.41 mmol), 1-iodo-4-trifluoromethoxybenzene (142mg, 0.493 mmol), Cs₂CO₃ (535 mg, 1.644 mmol), CuI (3 mg, 0.012 mmol),8-hydroxyquinoline (2 mg, 0.012 mmol), and DMF/H₂O (2 mL; 10:1 solution)were combined in a 10 mL CEM Microwave reaction vessel fitted withmagnetic stir bar and subjected to microwave irradiation at 150° C. for30 min. The contents were then filtered and concentrated to drynessaffording the 1,3-diphenyl triazole intermediate (18 mg, 13%).

Example 16 Preparation of4-[1-(4-pentafluoroethylsulfanylphenyl)-1H-[1,2,4]triazol-3-yl]-benzonitrile

Step 1. 1-Bromo-4-pentafluoroethylsulfanylbenzene. The title compoundwas prepared using perfluoroalkylation conditions originally describedby Popov et. al. J. Fluorine Chem. 1982, 21, 365. To a solution of4-bromobenzenethiol (500 mg, 2.64 mmol, 1.00 eq) and triethylbenzylammonium chloride (60 mg, 0.26 mmol, 0.10 eq) in 10 mL of 1:1 Et₂O/NaOH(25% aq) at 0° C. was bubbled 1,1,1,2,2-pentafluoro-2-iodoethane gas for30 min (>5 eq). During this time a UV lamp was directed at the reactionvessel while the temperature was maintained below 10° C. by intermittentuse of an ice bath. The contents were then warmed to room temperature,extracted into Et₂O (300 mL), dried (MgSO₄), and concentrated underreduced pressure. A portion of this crude material was used insubsequent reactions without further purification (200 mg residue: 120mg product, 0.39 mmol, 1.2 eq).

Step 2. 4-[1-(4-Pentafluoroethylsulfanylphenyl)-1H-[1,2,4]triazol-3-yl]-benzonitrile. Coupling with4-(1H-[1,2,4]triazol-3-yl)-benzonitrile as described above gave4-[1-(4-pentafluoroethylsulfanylphenyl)-1H-[1,2,4]triazol-3-yl]-benzonitrile(70 mg, 46%).

Example 17 Preparation of 4-[1-(4-pentafluoroethyloxy-phenyl)-1H-[1,2,4]triazol-3-yl]-benzaldehyde

Step 1. A solution of 3-p-tolyl-1H-[1,2,4]triazole (4.85 g, 30.5 mmol),4-bromophenyl pentafluoroethyl ether (10.0 g, 34.4 mmol), Cs₂CO₃ (25 g,77 mmol), CuI (1.25 g, 6.5 mmol) and 8-hydroxyquinoline (0.35 g, 2.4mmol) in 9:1 DMF/H₂O (50 mL) was stirred vigorously and heated to 130°C. (internal temperature) for 20 h. The solution was then cooled, pouredinto water, and acidified with 2 N HCl to pH 2. Ether (250 mL) was thenadded and the solution was shaken and filtered before separating layers.The organic layer was dried and concentrated, and the resulting gummysolid was heated with hexanes (100 mL). The hot hexane layer wasdecanted from insoluble residue, the resulting solution cooled to 0° C.and the precipitated solid was filtered and air-dried to furnish1-(4-pentafluoroethyloxy-phenyl)-3-p-tolyl-1H-[1,2,4]triazole (7.0 g,61% based on starting triazole) as an off-white solid: mp 130-132° C.;ESIMS m/z 370.8 (M+H).

Step 2. The product from Step 1 (7.0 g, 18.7 mmol) was dissolved inacetonitrile (200 mL) and stirred at ambient temperature while cericammonium nitrate (32 g, 58 mmol) in water (60 mL) was added in portionsover 10 min. The solution was then heated to reflux for 4 h, cooled, anddiluted with water (200 mL). The solution was extracted with ether(2×200 mL), and the combined organic layer was dried and concentrated togive an orange oil. This material was dissolved in dioxane (40 mL) andtreated with a solution of KOH (5 g, 90 mmol) in water (20 mL). Thesolution was heated to reflux for 2 h, then cooled and diluted withwater (100 mL). The aldehyde precipitated and was collected byfiltration. Recrystallization from MeOH/H₂O gave the pure aldehyde as awhite solid (2.2 g, 30%): mp 137-144° C. ¹H NMR (300 MHz, CDCl₃) δ 10.1(s, 1H), 8.65 (s, 1H), 8.40 (d, J=8.4 Hz, 2H), 8.0 (d, J=8.4 Hz, 2H),7.85 (d, J=9 Hz, 2H), 7.45 (d, J=9 Hz, 2H); ESIMS m/z 384.2 (M+H).

Example 18 Preparation of4-[1-(4-pentafluoroethyloxy-phenyl)-1H-[1,2,4]triazol-3-yl]-benzoic acid

A solution of4-[1-(4-pentafluoroethyloxy-phenyl)-1H-[1,2,4]triazol-3-yl]-benzaldehyde(1.7 g, 4.4 mmol), sodium bromate (2.1 g, 13.9 mmol) and sodiumbisulfate (0.53 g, 4.5 mmol) in acetonitrile (50 mL) was heated toreflux for 5 h, during which time a voluminous precipitate formed. Thesolution was then cooled and poured into water (100 mL), filtered, anddried to furnish the acid (1.67 g) as a white solid: mp 225° C.; ¹H NMR(300 MHz, CDCl₃) δ 10.1 (s, 1H), 8.63 (s, 1H), 8.35 (d, J=8.4 Hz, 2H),8.5 (d, J=8.4 Hz, 2H), 7.85 (d, J=9 Hz, 2H), 7.43 (d, J=9 Hz, 2H); ESIMSm/z 399.2 (M+FI').

Example 19 Preparation of4-[1-(4-pentafluoroethyloxy-phenyl)-1H-[1,2,4]triazol-3-yl]-benzoylazide

A solution of4-[1-(4-pentafluoroethyloxy-phenyl)-1H-[1,2,4]triazol-3-yl]-benzoic acid(1.67 g, 4.2 mmol), diphenylphosphoryl azide (1.26 g, 4.58 mmol) andtriethylamine (0.5 g, 5 mmol) in dry t-BuOH (10 mL) was heated to 75° C.for 90 min, resulting in dissolution of the starting acid and subsequentprecipitation of the azide. The cooled solution was then poured onto ice(10 g), and the resulting mixture was filtered and dried to furnish theazide (0.80 g) as a white solid: mp 112-115° C. dec; ¹H NMR (300 MHz,CDCl₃) δ 8.62 (s, 1H), 8.33 (d, J=8.4 Hz, 2H), 8.16 (d, J=8.4 Hz, 2H),7.85 (d, J=9 Hz, 2H), 7.42 (d, J=9 Hz, 2H); ESIMS m/z 425 (M+H).

Example 20 Preparation of4-[1-(4-butylphenyl)-1H-[1,2,4]triazol-3-yl]-benzonitrile

A solution of 4-n-butyl phenyl hydrazine (1.0 g, 5 mmol) and4-cyanobenzaldehyde (0.8 g, 6.0 mmol) in i-PrOH (15 mL)was heated on asteam bath for 2 h and then was cooled and diluted with water (5 mL).The resulting orange solid was filtered and air-dried to give thehydrazone (1.30 g) as a yellow solid, mp 107° C. A solution of thishydrazone (1.1 g, 4.0 mmol) and NCS (0.67 g, 5 mmol) in i-PrOH (20 mL)was stirred under nitrogen at ambient temperature for 2 h, during whichtime the original solid dissolved and a new solid formed. The resultingorange solution was then treated with tetrazole (0.45 g, 6.4 mmol) andtriethylamine (960 μL, 7.0 mmol). The orange-brown solution was heatedat reflux for 2 h. The solution was then cooled, diluted with water (25mL), extracted with EtOAc, dried, concentrated, and purified bychromatography (Biotage, 4:1 hexane:EtOAc) to give the triazole (0.42 g,35%) as an off-white solid: mp 124° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.58(s, 1H), 8.33 (d, J=8 Hz, 2H), 7.78 (d, J=8 Hz, 2H), 7.64 (d, J=8.2 Hz,2H), 7.33 (d, J=8.2 Hz, 2H), 2.70 (t, J=7.8 Hz, 2H), 1.63 (m, 2H), 1.38(m, 2H), 0.95 (t, J=7.5 Hz, 3H); ESIMS m/z 303.1.

Example 21 Preparation of4-[1-(4-pentafluoroethyl-phenyl)-1H-[1,2,4]triazol-3-yl]-benzaldehyde

Step 1. 1-(4-Pentafluoroethyl-phenyl)-3-p-tolyl-1H-[1,2,4]triazole.Pentafluoroethyl iodide (521 mg, 2.12 mmol) was condensed into a vialcontaining 1-bromo-4-iodobenzene (300 mg, 1.06 mmol), copper(0) powder(135 mg, 2.12 mmol), and DMSO (5 mL). The vial was then sealed andsubjected to microwave irradiation at 150° C. for 60 min. GC-MS provedconsumption of the starting material yielding both1-bromo-4-pentafluoroethylbenzene and 1-iodo-4-pentafluoroethylbenzeneintermediates. The mixture (1.06 mmol) was transferred to a 250 mL roundbottom flask and 3-p-tolyl-1H-[1,2,4]triazole (169 mg, 1.06 mmol),Cs₂CO₃ (1.38 g, 4.24 mmol), CuI (202 mg, 1.06 mmol), 8-hydroxyquinoline(2 mg, 0.011 mmol), and DMF/H₂O (12 mL; 10:1 solution) were added. Thesolution was stirred at reflux at 160° C. for 6 h. Upon completion, thecooled contents were poured into H₂O and precipitation was allowed for 1h. The precipitate was collected by vacuum filtration and driedovernight in a 45° C. vacuum oven. The crude1-(4-pentafluoroethylphenyl)-3-p-tolyl-1H-[1,2,4]triazole intermediatewas used in step 2 without further purification.

Step 2. Oxidation to the aldehyde. Ammonium cerium(IV) nitrate (3.32 g,4.24 mmol) and the intermediate from Step 1 were combined in a roundbottom flask with acetonitrile and water (20 mL; 1:1). The solution wasstirred at reflux at 110° C. for 4 h, affording a mixture of the3-(4-nitrooxymethyl-phenyl)-1-(4-pentafluoroethyl-phenyl)-1H-[1,2,4]triazole and 4-[1-(4-pentafluoroethyl-phenyl)-1H-[1,2,4]triazol-3-yl]-benzaldehyde intermediates. Theacetonitrile was removed under vacuum and the crude intermediateprecipitates were collected by filtration. The material was thencombined with powdered KOH (178 mg, 3.18 mmol) in dioxane and water (10mL; 1:1) and was stirred at reflux at 105° C. for 90 min before thedioxane was removed under vacuum allowing precipitation of theintermediate from water. The4-[1-(4-pentafluoroethyl-phenyl)-1H-[1,2,4]triazol-3-yl]-benzaldehydeintermediate was collected by filtration (35 mg, 0.095 mmol, 9% overallfrom 4-tolyl triazole).

Example 22 Preparation of trifluoromethanesulfonic acid4-[3-(4-formyl-phenyl)-[1,2,4]triazol-1-yl]-phenyl ester

Step 1. 1-(4-Methoxyphenyl)-3-p-tolyl-1H-[1,2,4]triazole was prepared bycoupling 3-p-tolyl-1H-[1,2,4]triazole with 4-iodoanisole underconditions described in Step 1 of the previous example. This materialwas then demethylated using conditions described in Hitchcock et al.Synlett 2006, 2625. Boron tribromide (1 M solution in hexanes; 1.67 mL,1.67 mmol) was added dropwise to a solution of1-(4-methoxyphenyl)-3-p-tolyl-1H-[1,2,4]triazole (300 mg, 1.28 mmol) inCH₂Cl₂ (10 mL) at 0° C. under N₂. After addition was complete, thevessel was warmed to ambient temperature before refluxing at 40° C. for6 h. The cooled contents were then quenched with H₂O before removal ofthe CH₂Cl₂ and partitioning between EtOAc and water. The organic layerwas collected, washed with brine, dried (MgSO₄), concentrated, andpurified via chromatography (3:1:1, hexanes:EtOAc:acetone) to afford the4-(3-p-tolyl-[1,2,4]triazol-1-yl)-phenol intermediate (219 mg, 0.872mmol, 68%). Trifluoromethanesulfonic anhydride (0.16 mL, 0.96 mmol) wasadded dropwise to a solution of the phenol and4-tert-butyl-2,6-dimethylpyridine (142 mg, 0.872 mmol) in CH₂Cl₂ (10 mL)at 0° C. under N₂. The vessel was warmed to ambient temperature beforethe solvent was removed under reduced pressure and the residue purifiedvia chromatography (2:2:1, hexanes:EtOAc:acetone) affording thetrifluoromethanesulfonic acid 4-(3-p-tolyl-[1,2,4]triazol-1-yl)-phenylester intermediate (304 mg, 0.794 mmol, 91%).

Step 2. Oxidation of the 4-methyl intermediate above to thecorresponding aldehyde was carried out using ammonium cerium(IV) nitrateunder conditions described in Step 2 of the previous example.

Example 23 Preparation of4-[5-(4-trifluoromethylphenyl)-1H-[1,2,4]triazol-3-yl]

Terephthalonitrile (115 mg, 0.90 mmol), 4-trifluoromethylbenzoic acidhydrazide (92 mg, 0.450 mmol), K₂CO₃ (31 mg, 0.225 mmol), and n-butylalcohol (−2 mL) were combined in a 10 mL CEM Microwave reaction vialfitted with magnetic stir bar and subjected to microwave irradiation at150° C. for 30 min. The contents were then filtered and concentrated todryness. Chromatography (3:1 hexanes/EtOAc) afforded the 1,2,4-triazolenitrile (72 mg, 0.230 mmol, 51%).

Example 24 Preparation of4-[1-(3,4-dichlorophenyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-benzonitrile

Step 1. 4-Cyanophenyl-oxo-acetic acid. A round bottom flask equippedwith mechanical stirrer and reflux condenser was charged withp-cyanoacetophenone (5 g, 34.44 mol), SeO₂ (9.55 g, 86.1 mmol), andpyridine (−100 mL). The mixture was stirred at reflux for 6 h beforeprecipitates were removed by filtration and the filtrate was chargedwith 10% HCl (aq) (20 mL). The filtrate was extracted into EtOAc (3×50mL) and the combined organic layers were further extracted into nearlysaturated NaHCO₃. The aqueous layer was then carefully made acidic(pH=1) with conc. HCl affording a small crop of the desired product. Theremainder of the oxo acetic acid was obtained by extracting into EtOAc,drying (MgSO₄), and concentration (1.69 g, 28%).

Step 2.4-[1-(3,4-Dichlorophenyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-benzonitrile.A suspension of 4-cyanophenyl-oxo-acetic acid (100 mg, 0.571 mmol),(3,4-dichlorophenyl)hydrazine hydrochloride (122 mg, 0.571 mmol), 12.1 NHCl (5 μL, 0.057 mmol), and H₂O (˜10 mL) in a 25 mL reaction vial wasstirred vigorously at ambient temperature for 24 h. The hydrazone wasobtained by vacuum filtration and placed into a 100 mL round bottomflask with a magnetic stir bar. The flask was then supplemented withtriethylamine (0.08 mL, 0.571 mmol), diphenylphosphoryl azide (157 mg,0.571 mmol), and toluene (20 mL) before heating at 110° C. for 1 h. Uponcooling the contents were quenched with 10% NaOH (aq) and made acidic(pH 1) with conc. HCl. Precipitation was allowed for 15 min before theintermediate was obtained by vacuum filtration and dried overnight in a45° C. vacuum oven (16 mg, 8%).

Example 25 Preparation of4-[1-(4-Chlorophenyl)-1H-[1,2,3]triazol-4-yl]-benzonitrile

Following the procedure published by Feldman et al. (Org. Lett. 2004, 6,3897), a suspension of 4-ethynylbenzonitrile (50 mg, 0.393 mmol),1-chloro-4-iodobenzene (94 mg, 0.393 mmol), L-proline (9 mg, 0.079mmol), ascorbic acid (7 mg, 0.039 mmol), NaN₃ (31 mg, 0.472 mmol), CuSO₄(3 mg, 0.020 mmol), and Na₂SO₄ (11 mg, 0.079 mmol) in DMSO (1.5 mL) washeated at 65° C. for 24 h. Upon cooling the mixture was diluted with H₂Oand stirred for 30 min at ambient temperature. The intermediate4-[1-(4-chlorophenyl)-1H[1,2,3]triazol-4-yl]-benzonitrile (54 mg, 48%)was then obtained by vacuum filtration after washing with copiousvolumes of H₂O and 20% NH₄OH (−20 mL).

Example 26 Preparation of4-[5-(4-trifluoromethylphenyl)-tetrazol-2-yl]-benzaldehyde

This aldehyde was prepared from 4-trifluoromethylbenzaldehyde byfollowing the route described in Roppe et al. J. Med. Chem. 2004, 47,4645.

Example 27 Preparation of4-[5-(4-trifluoromethoxyphenyl)-pyridin-3-yl]-benzaldehyde

Step 1. 3,5-Dibromopyridine (4.4 mmol), 4-trifluoromethoxyphenyl boronicacid (5.1 mmol), tetrakis(triphenylphosphine)palladium(0) (0.04 mmol), 2M potassium carbonate (8.44 mmol) and dioxane (21 mL) were combined in avial and heated by microwave for 10 min at 150° C. The reaction mixturewas taken up in ether and washed with brine. The ether layer was driedover magnesium sulfate, was filtered and the solvent removed in vacuo.The crude mixture was purified by silica gel chromatography to yield3-bromo-5-(4-trifluoromethoxyphenyl)-pyridine (130 mg) as a yellowsolid: ¹H NMR (400 MHz, CDCl₃) δ 8.71 (m, 2H), 8.00 (t, J=2.1 Hz, 1H),7.58 (d, J=8.8 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H); EIMS m/z 317 (M⁺).

Step 2. The compound was prepared by palladium-catalyzed arylation ofthe product of step 1 with 4-formylphenyl boronic acid.

Example 28 Preparation of4-[4-(4-trifluoromethoxyphenyl)-pyridin-2-yl]-benzaldehyde

Step 1. The compound was prepared by palladium-catalyzed arylation of2-chloro-4-iodopyridine with 4-trifluoromethoxyphenyl boronic acid.

Step 2. 2-Chloro-4-(4-trifluoromethoxyphenyl)-pyridine (0.55 mmol)starting from 2-chloro-4-iodopyridine, 4-formylphenyl boronic acid (0.82mmol), tetrakis(triphenylphosphine)palladium(0) (0.005 mmol), 2 Mpotassium carbonate (0.55 mL) and dioxane (3 mL) were combined in a vialand irradiated by microwave for 15 min at 150° C. The reaction mixturewas taken up in EtOAc and washed with brine. The organic layer was driedover magnesium sulfate, was filtered and the solvent removed in vacuo.Purification by silica gel chromatography (EtOAc/hexanes) yielded theproduct (120 mg) as an off-white solid: ¹H NMR (400 MHz, CDCl₃) δ 10.11(s, 1H), 8.81 (d, J=4.8 Hz, 1H), 8.24 (d, J=8.7 Hz, 2H), 8.03 (d, J=8.4Hz, 2H), 7.96 (m, 1H), 7.73 (d, J=9.0 Hz, 2H), 7.49 (dd, J=5.3, 1.8 Hz,1H), 7.37 (d, J=8.1 Hz, 2H); EIMS m/z 343 (M⁺).

Example 29 Preparation of4-[6-(4-trifluoromethoxyphenyl)-pyridin-2-yl]-benzaldehyde

Step 1. 4-(6-Bromopyridin-2-yl)-benzaldehyde (0.31 mmol) was prepared asin Puglisi et al. Eur. J. Org. Chem. 2003, 8, 1552-1558.

Step 2. 4-[6-(4-Trifluoromethoxyphenyl)-pyridin-2-yl]-benzaldehyde.4-(6-Bromo-pyridin-2-yl)-benzaldehyde (0.31 mmol),4-trifluoromethoxyphenyl boronic acid (0.46 mmol),tetrakis(triphenylphosphine)palladium(0) (0.003 mmol), 2 M potassiumcarbonate (0.31 mL) and dioxane (2 mL) were combined in a vial andirradiated by microwave for 10 min at 150° C. The reaction mixture wastaken up in ether and washed with brine. The organic layer was driedover magnesium sulfate, was filtered and the solvent removed in vacuo.Purification by silica gel chromatography (EtOAc/hexanes) yielded theproduct (80 mg) as an off-white solid: mp 109-112° C.; ¹H NMR (400 MHz,CDCl₃) δ 10.11 (s, 1H), 8.32 (d, J=8.5 Hz, 2H), 8.19 (d, J=8.1 Hz, 2H),8.03 (d, J=8.4 Hz, 2H), 7.89 (t, J=7.9 Hz, 1H), 7.79 (d, J=7.7 Hz, 1H),7.74 (d, J=8.0 Hz, 1H), 7.35 (d, J=8.3 Hz, 2H); EIMS m/z 343 (M⁺).

Example 30 Preparation of4-[6-(4-trifluoromethoxyphenyl)-pyrimidin-4-yl]-benzaldehyde

Step 1. 4-Chloro-6-(4-trifluoromethoxyphenyl)-pyrimidine was prepared bypalladium-catalyzed arylation of 4,6-dichloropyrimidine and4-trifluoromethoxyphenyl boronic acid: ¹H NMR (400 MHz, CDCl₃) δ 9.05(s, 1H), 8.14 (d, J=9.8 Hz, 2H), 7.74 (m, 1H), 7.36 (d, J=8.4 Hz, 2H);EIMS m/z 274 (M⁺).

Step 2. The compound was prepared by palladium-catalyzed arylation ofthe product of step 1 with 4-formylphenyl boronic acid: ¹H NMR (400 MHz,CDCl₃) δ 10.15 (s, 1H), 9.38 (d, J=0.9 Hz, 1H), 8.33 (d, J=8.4 Hz, 2H),8.23 (d, J=8.5 Hz, 2H), 8.16 (d, J=0.8 Hz, 1H), 8.08 (d, J=8.8 Hz, 2H),7.40 (d, J=8.1 Hz, 2H); EIMS m/z 344 (M⁺).

Example 31 Preparation of4-[2-(4-trifluoromethoxyphenyl)-pyrimidin-4-yl]-benzaldehyde

Step 1. 4-Chloro-2-(4-trifluoromethoxyphenyl)-pyrimidine. The titlecompound was prepared by palladium-catalyzed arylation of2,4-dichloropyrimidine and 4-trifluoromethoxyphenyl boronic acid: mp70-73° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.68 (d, J=5.6 Hz, 1H), 8.16 (d,J=9.1 Hz, 2H), 7.65 (d, J=5.3 Hz, 1H), 7.36 (dd, J=9.2, 0.9 Hz, 2H);EIMS m/z 274 (M⁺).

Step 2. The compound was prepared by palladium-catalyzed arylation ofthe product of step 1 with 4-formylphenyl boronic acid: ¹H NMR (400 MHz,CDCl₃) δ 10.13 (s, 1H), 8.91 (d, J=4.8 Hz, 1H), 8.74 (d, J=8.5 Hz, 2H),8.28 (d, J=8.4 Hz, 2H), 8.03 (d, J=8.4 Hz, 2H), 7.65 (d, J=5.3 Hz, 1H),7.39 (d, J=8.6 Hz, 2H); EIMS m/z 344 (M⁺).

Example 32 Preparation of4-[4-(4-trifluoromethoxyphenyl)-pyrimidin-2-yl]-benzaldehyde

Step 1. 4-(4-Chloropyrimidin-2-yl)-benzaldehyde. The compound wasprepared by palladium-catalyzed arylation of 2,4-dichloropyrimidine and4-formylphenyl boronic acid: ¹H NMR (400 MHz, CDCl₃) δ 10.13 (s, 1H),8.74 (d, J=5.0 Hz, 1H), 8.27 (d, J=7.8 Hz, 2H), 8.04 (d, J=7.9 Hz, 2H),7.74 (m, 1H); EIMS m/z 218 (M⁺).

Step 2. The compound was prepared by palladium-catalyzed arylation ofthe product of Step 1 with 4-trifluoromethoxyphenyl boronic acid: ¹H NMR(400 MHz, CDCl₃) δ 10.14 (s, 1H), 8.91 (d, J=4.2 Hz, 1H), 8.63 (d, J=8.5Hz, 2H), 8.37 (d, J=8.4 Hz, 2H), 8.06 (d, J=8.8 Hz, 2H), 7.67 (d, J=5.4Hz, 1H), 7.35 (d, J=8.7 Hz, 2H); EIMS m/z 344 (M⁺).

Example 33 Preparation of4-[6-(4-trifluoromethoxyphenyl)-pyrazin-2-yl]-benzaldehyde

Step 1. 2-Chloro-6-(4-trifluoromethoxyphenyl)-pyrazine. The compound wasprepared by palladium-catalyzed arylation of 2,6-dichloropyrazine and4-trifluoromethoxyphenyl boronic acid: mp 58-60° C.; ¹H NMR (400 MHz,CDCl₃) δ 8.94 (s, 1H), 8.57 (s, 1H), 8.10 (d, J=9.0 Hz, 2H), 7.37 (d,J=8.4 Hz, 2H); EIMS m/z 274 (M⁺).

Step 2. The compound was prepared by palladium-catalyzed arylation ofthe product of step 1 with 4-formylphenyl boronic acid: ¹H NMR (400 MHz,CDCl₃) δ 10.13 (s, 1H), 9.07 (s, 1H), 9.03 (s, 1H), 8.33 (d, J=8.1 Hz,2H), 8.21 (d, J=8.7 Hz, 2H), 8.07 (d, J=7.6 Hz, 2H), 7.40 (d, J=8.3 Hz,2H); EIMS m/z 344 (M⁺).

Example 34 Preparation of4-[2-(4-trifluoromethoxyphenyl)-pyrimidin-5-yl]-benzaldehyde

Step 1. 4-(2-Chloropyrimidin-5-yl)-benzaldehyde. The compound wasprepared by palladium-catalyzed arylation of 2,5-dichloropyrimidine and4-formylphenyl boronic acid.

Step 2. 4-(2-Chloropyrimidin-5-yl)-benzaldehyde (0.92 mmol),4-trifluoromethoxyphenyl boronic acid (1.10 mmol),dichlorobis(triphenylphosphine)palladium(II) (0.01 mmol), 2 M potassiumcarbonate (0.92 mL) and dioxane (5 mL) were combined in a vial andirradiated by microwave for 10 min at 150° C. The organic layer from thereaction mixture was loaded directly onto silica and dried in vacuo.Purification by silica gel chromatography (EtOAc/hexanes) yielded theproduct (140 mg) as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 10.11 (s,1H), 9.07 (s, 2H), 8.57 (d, J=9.0 Hz, 2H), 8.07 (d, J=8.5 Hz, 2H), 7.82(d, J=8.3 Hz, 2H), 7.35 (d, J=8.3 Hz, 2H); EIMS m/z 344 (M⁺).

Example 35 Preparation of4-[5-(4-trifluoromethoxyphenyl)-pyrimidin-2-yl]-benzaldehyde

Step 1. 2-Chloro-5-(4-trifluoromethoxyphenyl)-pyrimidine. The compoundwas prepared by palladium-catalyzed arylation of 2,5-dichloropyrimidinewith 4-trifluoromethoxyphenyl boronic acid.

Step 2. 2-Chloro-5-(4-trifluoromethoxyphenyl)-pyrimidine (4.22 mmol),4-formylphenyl boronic acid (5.1 mmol),dichlorobis(triphenylphosphine)palladium(II) (0.05 mmol), 2 M potassiumcarbonate (4.2 mL) and dioxane (21 mL) were combined in a vial andirradiated by microwave for 20 min at 150° C. The organic layer from thereaction mixture was loaded directly onto silica and dried in vacuo.Purification by silica gel chromatography (EtOAc/hexanes) yielded theproduct (75 mg) as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 10.13 (s,1H), 9.06 (s, 2H), 8.68 (d, J=8.8 Hz, 2H), 8.03 (d, J=8.3 Hz, 2H), 7.68(d, J=8.8 Hz, 2H), 7.40 (d, J=8.7 Hz, 2H); EIMS m/z 344 (M⁺).

Example 36 Preparation of4-heptafluoropropyl-6-(4-nitrophenyl)-2-(4-trifluoromethylphenyl)-pyrimidine

Step 1.4-Heptafluoropropyl-6-(4-nitrophenyl)-2-(4-trifluoromethylphenyl)-pyrimidine.A solution of4-heptafluoropropyl-2-methylsulfanyl-6-(4-nitrophenyl)-pyrimidine (1.20g, 2.90 mmol; prepared from1-(4-nitrophenyl-4,4,5,5,6,6,6-heptafluorohexane-1,3-dione according toGreen et al. WO 200138311 A2), 4-trifluoromethylphenylboronic acid(0.608 g, 3.2 mmol), trifurylphosphine (114 mg, 0.49 mmol), and copper(II) 2-thiophenecarboxylate (750 mg, 3.9 mmol) were combined in dry THF(15 mL) and heated to 50° C. The catalysttris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (60 mg, cat)was then added in three portions over 3 h, and the solution was thenallowed to stir at 50° C. overnight. Concentration and chromatography(Biotage, 5:1 hexane/CH₂Cl₂) furnished the title compound (0.60 g, 40%)as a light yellow solid: mp 191° C.; EIMS m/z 514.0 (M+H).

Step 2.4-Heptafluoropropyl-6-(4-aminophenyl)-2-(4-trifluoromethylphenyl)-pyrimidine.A solution of4-heptafluoropropyl-2-(4-trifluoromethylphenyl)-6-(4-nitrophenyl)-pyrimidine(0.18 g, 0.35 mmol), iron powder (0.20 g, 3.5 mmol), ferric ammoniumsulfate (0.15 g, 0.3 mmol) in 3:1 EtOH/water was heated on a steam bathfor 3 h. Then it was cooled, diluted with Et₂O (50 mL), filtered throughCelite®, and concentrated to give the aniline as a yellow solid: ¹H NMR(300 MHz, CDCl₃) δ 8.75 (d, J=8 Hz, 2H), 8.18 (d, J=8 Hz, 2H), 7.90 (s,1H), 7.80 (d, J=8 Hz, 2H), 6.82 (d, J=8 Hz, 2H), 4.20 (s, 2H).

Example 37 Preparation of4-trifluoromethyl-6-(4-aminophenyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine

Step 1.4-Trifluoromethyl-6-(4-nitrophenyl)-2-(4-trifluoromethylphenyl)-pyrimidine.A solution of4-trifluoromethyl-2-methylsulfanyl-6-(4-nitrophenyl)-pyrimidine (1.25 g,4.0 mmol; prepared from 1-(4-nitrophenyl-4,4,4-trifluorobutane-1,3-dioneaccording to Green et al. WO 200138311 A2),4-trifluoromethylphenylboronic acid (0.95 g, 5.0 mmol),trifurylphosphine (140 mg, 0.60 mmol), and copper (II)2-thiophenecarboxylate (1.05 g, 5.0 mmol) were combined in dry THF (25mL) and heated to 52° C. The catalysttris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (100 mg) wasthen added in three portions over 3 h, and the solution was then allowedto stir at 50° C. for 12 h. Concentration and chromatography (Biotage,4:1 hexane/CH₂Cl₂) furnished the title compound (0.67 g, 41%) as a lightyellow solid: mp 162° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.75 (d, J=8 Hz,2H), 8.41 (s, 4H), 8.03 (s, 1H), 7.80 (d, J=8 Hz, 2H); EIMS m/z 414.1(M+H).

Step 2.4-Trifluoromethyl-6-(4-aminophenyl)-2-(4-trifluoromethylphenyl)pyrimidine.A solution of4-trifluoromethyl-2-(4-trifluoromethylphenyl)-6-(4-nitrophenyl)pyrimidine(0.50 g, 1.2 mmol), iron powder (0.50 g, 9 mmol), ferric ammoniumsulfate (0.5 g, 1.0 mmol) in 3:1 EtOH-water (30 mL) was heated on asteam bath for 3 h. Then it was cooled, diluted with diethyl ether (50mL), filtered through Celite®, and concentrated. The crude amine waspurified by Biotage column (4:1:1 Hexanes/EtOAc/CH₂Cl₂) to give pureaniline (0.22 g). This material was used directly in the formation ofthe corresponding carbamate: ¹H NMR (300 MHz, CDCl₃) δ 8.75 (d, J=8 Hz,2H), 8.16 (d, J=8 Hz, 2H), 7.81 (s, 1H), 7.77 (d, J=8 Hz, 2H), 6.82 (d,J=8 Hz, 2H), 4.15 (s, 2H).

Example 38 Preparation of4-[2-(4-trifluoromethylphenyl)-pyrimidin-4-yl]-phenylamine

Step 1. 4-(4-Nitrophenyl)-2-(4-trifluoromethylphenyl)-pyrimidine. Tosodium metal (82.7 mg, 3.60 mmol) dissolved in absolute EtOH (3 mL) wasadded 4-trifluoromethylbenzamidine hydrochloride dihydrate (938 mg, 3.60mmol) followed by EtOH (4 mL). After 30 min,3-dimethylamino-1-(4-nitrophenyl)-propenone (498 mg, 2.26 mmol) wasadded, and the mixture was heated at reflux approximately 66 h and wasthen allowed to cool. The mixture was concentrated to a tan solid whichwas triturated under saturated sodium bicarbonate. The solid wascollected and air dried to give 937 mg. It was then dissolved inchloroform/EtOAc and was passed over silica gel eluting with 7:3chloroform/EtOAc to afford the title compound (710 mg, 91%): mp175-176.5° C.; ¹H NMR δ 9.01 (d, J=5.3 Hz, 1H), 8.73 (d, J=8.2 Hz, 2H),8.43 (s, 4H), 7.82 (d, J=8.1 Hz, 2H), 7.76 (d, J=5.2 Hz, 1H); EIMS m/z345 (M⁺, 100), 299 (57). Anal. Calcd. for C₁₇H₁₀F₃N₃O₂: C, 59.13; H,2.92; N, 12.17. Found: C, 58.82; H, 2.63; N, 11.98.

Step 2. 4-[2-(4-Trifluoromethylphenyl)-pyrimidin-4-yl]-phenylamine. Amixture of 4-(4-nitrophenyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine(670 mg, 1.94 mmol) and 10% Pd/C (75 mg) in EtOH (30 mL) was placed on aParr shaker at 40 psi hydrogen gas at room temperature. After 7 h themixture was filtered through Celite® and the EtOH was removed in vacuo.The residue was partitioned between EtOAc and saturated NaHCO₃, and theorganic phase was dried (MgSO₄). Concentration gave a solid which wasdissolved in EtOAc and was filtered through a plug of silica gel.Concentration gave the title compound (500 mg, 82%): mp 166-167° C.; ¹HNMR δ δ 8.75 (d, J=5.30 Hz, 1H), 8.67 (d, J=8.3 Hz, 2H), 8.10 (d, J=8.9Hz, 2H), 7.75 (d, J=7.9 Hz, 2H), 7.54 (d, J=5.3 Hz, 1H), 6.80 (d, J=8.6Hz, 2H), 4.03 (br s, 2H); MS (API-ES+) 316 ([M+H]⁺, 100). Anal. Calcd.for C₁₇H₁₂F₃N₃: C, 64.76; H, 3.84; N, 13.33. Found: C, 64.37; H, 3.71;N, 13.08.

Example 39 Preparation of2-chloro-4-[3-(4-trifluoromethylphenyl)-[1,2,4]triazol-1-yl]-phenylamine

Step 1.1-(3-Chloro-4-nitrophenyl)-3-(4-trifluoromethyl-phenyl)-1H-[1,2,4]triazole.A solution of NBS (180 mg, 1 mmol) in CH₂Cl₂ (4 mL) was stirred undernitrogen at 0° C. while dimethyl sulfide (110 mg, 1.8 mmol) was addedvia syringe. The solution, which forms a white solid, was then cooled to−20° C., and(N-(3-chloro-4-nitrophenyl)-N-(4-trifluoromethyl-benzylidene)-hydrazine(200 mg, 0.58 mmol) in CH₂Cl₂ (4 mL) was added. The solution was allowedto warm to ambient temperature and stirred for an additional 2 h. Theresulting orange solution was then diluted with CH₂Cl₂ (25 mL) andwashed with water and brine before drying and concentrating. Theresulting orange solid hydrazonyl bromide (150 mg) was then treateddirectly with tetrazole (25 mg, 0.35 mmol) and triethylamine (50 μL,0.35 mmol) in absolute EtOH (5 mL). The resulting orange-brown solutionwas heated at reflux for 2 h. TLC showed that the initial bromide wasfirst converted into two yellow intermediates, which then disappearedand were replaced by a single, colorless spot. The orange solution wasthen diluted with water (10 mL), yielding a tan-yellow solid which wasfiltered, air-dried, and recrystallized from toluene to give ayellow-tan solid (60 mg): mp 185° C. ¹H NMR (300 MHz, CDCl₃) δ 8.60 (s,1H), 8.41 (d, J=8.7 Hz, 1H), 8.33 (d, J=7.5 Hz, 2H), 7.90 (d, J=2 Hz,1H), 7.70 (d, J=7.5 Hz, 2H), 7.65 (dd, J=8.7, 2 Hz, 1H); EIMS m/z 368.9.Anal. Calcd. for C₁₅H₈ClF₃N₄O₂: C, 48.86; H, 2.19; N, 15.20. Found: C,48.39; H, 2.61; N, 14.91.

Step 2.2-Chloro-4-[3-(4-trifluoromethylphenyl)-[1,2,4]triazol-1-yl]-phenylamine.A solution of the nitrophenyl derivative (0.75 g, 2.0 mmol) in MeOH (7mL) and water (3 mL) was treated with iron powder (0.7 g, 12.5 mmol) andferrous ammonium sulfate (hexahydrate; 0.7 g, 1.8 mmol). The solutionwas heated on a steam bath for 3 h, whereupon TLC showed completeconversion to a more polar, fluorescent product. The solution was cooledand filtered, and the filtrate was concentrated in vacuo. Purificationby chromatography through a short plug of silica gel (7:2:1hexane/EtOAc/CH₂Cl₂) gave the amine (0.55 g) as a light tan solid: mp148° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.40 (s, 1H), 8.31 (d, J=8.4 Hz, 1H),7.72 (d, J=8.4 Hz, 2H), 7.69 (d, J=2 Hz, 1H), 7.42 (dd, J=8.5, 2 Hz,1H), 6.9 (d, J=8.4 Hz, 1H); EIMS m/z 340.4, 342.3 (M+H). Anal. Calcd.for C₁₅H₁₀ClF₃N₄: C, 53.19; H, 2.98; N, 16.83. Found: C, 52.90 H, 3.10;N, 16.83.

Example 40 Preparation of4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]

Step 1.1-(4-Trifluoromethoxyphenyl)-3-(4-nitrophenyl)-1H-[1,2,4]triazole. Asolution of NBS (0.70 g, 3.9 mmol) in CH₂Cl₂ (25 mL) was stirred undernitrogen at 0° C. while dimethyl sulfide (0.40 g, 6.5 mmol) was addedvia syringe. The solution, which forms a white solid, was then cooled to−20° C., andN-(4-nitrobenzylidene)-N-(4-trifluoromethoxyphenyl)-hydrazine (0.70 g,2.15 mmol) in CH₂Cl₂ (10 mL) was added. The solution was allowed to warmto ambient temperature and stirred an additional 2 h. The resultingorange solution was then diluted with CH₂Cl₂ (25 mL) and washed withwater and brine before drying and concentrating. The resulting orangesolid hydrazonyl bromide (0.9 g) was then treated directly withtetrazole (154 mg, 2.2 mmol) and triethylamine (280 μL, 0.23 mmol) inabsolute EtOH (5 mL). The resulting orange-brown solution was heated atreflux for 2 h. TLC showed that the initial bromide was first convertedinto two yellow intermediates, which were replaced by a single,colorless spot. The orange solution was then concentrated and purifiedby chromatography (2:1:2 hexanes/EtOAc/CH₂Cl₂), yielding the titlecompound (0.30 g) as a light yellow solid: mp 147° C.; ¹H NMR (300 MHz,CDCl₃) δ 8.68 (s, 1H), 8.40 (d, J=5 Hz, 2H), 8.35 (d, J=5 Hz, 2H), 7.85(d, J=8 Hz, 2H), 7.42 (d, J=8 Hz, 2H); EIMS m/z 350 (M⁺, 100), 299 (57).

Step 2.4-[1-(4-Trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenylamine.Catalytic reduction using a Pd/C catalyst in EtOH under hydrogenatmosphere gave the corresponding aniline as a light grey solid: mp 160°C.; ¹H NMR (300 MHz, CDCl₃) δ 8.50 (s, 1H), 8.00 (d, J=8.4 Hz, 2H), 7.78(d, J=8.7 Hz, 2H), 7.35 (d, J=8 Hz, 2H), 6.76 (d, J=8.7 Hz, 2H), 3.9 (brs, 2H); EIMS m/z 321.

Example 41 Preparation of4-[1-(4-pentafluoroethyloxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenylamine

Step 1.1-(4-Pentafluoroethyloxyphenyl)-3-(4-nitrophenyl)-1H-[1,2,4]triazole. Aslurry of 3-(4-nitrophenyl)triazole (11.4 g, 60 mmol),1-iodo-4-pentafluoroethoxybenzene (20 g, 60 mmol), cesium carbonate(39.0 g, 120 mmol), CuI (3.5 g, 18 mmol), 8-hydroxyquinoline (2.0 g,13.8 mmol) and 9:1 DMF-H₂O (155 mL) was heated at 150° C. for 5 h andthen cooled. The contents of the round-bottomed flask were poured ontowater (150 mL) and extracted with Et₂O (2×100 mL). The organic layer wasdried and concentrated, and the solid residue recrystallized from MeOHand water to give the nitrotriazole (11.8 g, 49%) as a tan solid: mp170-175° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.68 (s, 1H), 8.40 (d, J=5 Hz,2H), 8.35 (d, J=5 Hz, 2H), 7.85 (d, J=8 Hz, 2H), 7.42 (d, J=5.2 Hz, 8Hz, 2H); EIMS m/z 400 (M⁺).

Step 2.4-[1-(4-Pentafluoroethyloxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenylamine.Catalytic reduction using a Pd/C catalyst in EtOH under hydrogenatmosphere gave the corresponding aniline as a light tan solid: mp 160°C.; ¹H NMR (300 MHz, CDCl₃) δ 8.55 (s, 1H), 8.00 (d, J=7 Hz, 2H), 7.78(d, J=8 Hz, 2H), 7.35 (d, J=8 Hz, 2H), 6.78 (d, J=8 Hz, 2H), 3.9 (br s,2H); EIMS m/z 371.

Example 42 Preparation of4-[1-(4-heptafluoropropyloxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenylamine

Step 1.1-(4-Heptafluoropropyloxyphenyl)-3-(4-nitrophenyl)-1H-[1,2,4]triazole. Aslurry of 3-(4-nitrophenyl)triazole (1.0 g, 5.2 mmol),1-iodo-4-heptafluoropropyloxybenzene (6.1 g, 15.8 mmol), cesiumcarbonate (10.0 g, 30.7 mmol), CuI (900 mg, 4.7 mmol), and8-hydroxyquinoline (500 mg, 3.4 mmol) in 9:1 DMF-H₂O (40 mL) was heatedat 150° C. for 12 h, then cooled and the contents poured onto water (50mL) and concentrated NH₄OH (50 mL). The blue solution was extracted withether (100 mL), and the organic layer was separated and filtered toremove some insoluble material, then dried and concentrated. The solidresidue was recrystallized from MeOH/water to furnish the nitrophenyltriazole (4.69 g) as a light tan solid: mp 114-116° C.; ¹H NMR (300 MHz,CDCl₃) δ 8.66 (s, 1H), 8.40 (m, 4H), 7.85 (d, J=8 Hz, 2H), 7.42 (d, J=8Hz, 2H); EIMS m/z 450.1 (M⁺).

Step 2.4-[1-(4-Heptafluoropropyloxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenylamine.Catalytic reduction under the conditions described above gave thecorresponding aniline as a light tan solid: mp 181-183° C.; ¹H NMR (300MHz, CDCl₃) δ 8.54 (s, 1H), 8.00 (d, J=8 Hz, 2H), 7.80 (d, J=8 Hz, 2H),7.40 (d, J=8 Hz, 2H), 6.78 (d, J=8 Hz, 2H), 3.9 (br s, 2H); EIMS m/z421.3 (M+1).

Example 43 Preparation of4-[4-(4-trifluoromethylphenyl)-imidazol-1-yl]-phenylamine

Step 1. 4-[4-(4-Trifluoromethylphenyl)-1H-imidazol-1-yl]-nitrobenzene.4-Trifluoromethylphenyl imidazole (1.43 g, 6.7 mmol), 4-fluoronitrobenzene (1.2 g, 8.5 mmol) and potassium carbonate (1.5 g, 10.9mmol) were combined in DMF (15 mL) and heated at 100° C. for 6 h. Thecooled solution was then poured onto water (100 mL), and the resultingsolid was filtered and air-dried to give the title imidazole (1.0 g) asa light yellow solid: mp 197° C. Anal. Calcd. for C₁₆H₁₀F₃N₃O₂: C,57.66; H, 3.02; N, 12.61. Found: C, 57.69; H, 3.01; N, 12.48.

Step 2. 4-[4-(4-Trifluoromethylphenyl)-imidazol-1-yl]-phenylamine.Catalytic reduction using a Pd/C catalyst in EtOH under hydrogenatmosphere gave the corresponding aniline as a light grey solid: mp142-143° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.90 (d, J=7 Hz, 2H), 7.75 (s,1H), 7.65 (d, J=7 Hz, 2H), 7.52 (s, 1H), 7.19 (d, J=8 Hz, 2H), 6.75 (d,J=8 Hz, 2H), 3.8 (br s, 2H); EIMS m/z 302.0.

Example 44 Preparation of4-[1-(4-trifluoromethylphenyl)-1H-imidazol-4-yl]-phenylamine

Step 1. 4-[4-(4-Trifluoromethylphenyl)-1H-imidazol-1-yl]-nitrobenzene.Prepared as in step 1 of the preceding example.

Step 2. 4-[1-(4-Trifluoromethylphenyl)-1H-imidazol-4-yl]-phenylamine.Catalytic reduction using a Pd/C catalyst in EtOH under hydrogenatmosphere gave the corresponding aniline as a light grey solid: mp 191°C.; ¹H NMR (400 MHz, CDCl₃) δ 7.92 (s, 1H), 7.76 (d, J=8 Hz, 2H), 7.66(d, J=4.5 Hz, 2H), 7.55 (s, 1H), 6.75 (d, J=4.5 Hz, 2H), 3.8 (br s, 2H);EIMS m/z 304.0. Anal. Calcd. for C₁₆H₁₂F₃N₃: C, 63.36; H, 3.99; N,13.85. Found: C, 63.14; H, 4.07; N, 13.52.

Example 45 Preparation of4-[1-(4-trifluoromethoxyphenyl)-1H-imidazol-4-yl]-phenylamine

Step 1. 4-(4-Nitrophenyl)-1-(4-trifluoromethoxyphenyl)-1H-imidazole. Theconditions described by Porretta et al. Farmaco, Edizione Scientifica1985, 40, 404 were used to convert 4-trifluoromethoxyaniline (5.3 g, 30mmol) and α-bromo-4-nitroacetophenone (3.7 g, 15 mmol) into theimidazole (2.1 g, 41%).

Step 2. 4-[1-(4-Trifluoromethoxyphenyl)-1H-imidazol-4-yl]-phenylamine.Catalytic reduction using a Pd/C catalyst in EtOH under hydrogenatmosphere gave the corresponding aniline as a light grey solid: mp 167°C.; ¹H NMR (300 MHz, CDCl₃) δ 7.83 (s, 1H), 7.64 (d, J=4.8 Hz, 2H), 7.47(d, J=4.4 Hz, 2H), 7.40 (s, 1H), 7.36 (d, J=4.8 Hz, 2H), 6.75 (d, J=4.4Hz, 2H), 3.5 (br s, 2H); EIMS m/z 320. Anal. Calcd. for C₁₆H₁₂F₃N₃O: C,60.19; H, 3.79; N, 13.16. Found: C, 59.91; H, 3.67; N, 13.03.

Example 46 Preparation of4-(4-aminophenyl)-2-(4-trifluoromethoxyphenyl)-2,4-dihydro-[1,2,4]triazol-3-one

Step 1.4-(4-Nitrophenyl)-2-(4-trifluoromethoxyphenyl)-2,4-dihydro-[1,2,4]triazol-3-one.The title compound was prepared according to the procedure in Henbach,DE 2724891 A1, 1978, with modifications to three steps: In the additionof the aniline, 4-nitroaniline was used instead of 3,5-dichloroanilineand dry THF was used as solvent instead of toluene. In the formation ofthe triazolinone ring, triphosgene (0.65 equiv) was used instead ofphosgene: mp 136-140° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.40 (d, J=8.8 Hz,2H), 8.05 (d, J=8.8 Hz, 2H), 7.99 (s, 1H), 7.89 (d, J=9.3 Hz, 2H), 7.32(d, J=9.3 Hz, 2H); ESIMS m/z 367 (M+H).

Step 2.4-(4-Aminophenyl)-2-(4-trifluoromethoxyphenyl)-2,4-dihydro-[1,2,4]triazol-3-one.The nitrophenyl triazolinone (0.037 g, 0.10 mmol) was dissolved inabsolute EtOH (1 mL) under N₂. To this was added tin(II) chloridedihydrate (0.114 g, 0.51 mmol), and the mixture was stirred at refluxfor 2 h. The mixture was cooled to 25° C., was poured onto ice-H₂O (25mL), and the aqueous mixture was brought to pH 9-10 with 1 N NaOH. Themixture was extracted with Et₂O (3×25 mL), and the combined organicextracts were dried (MgSO₄), filtered and concentrated to give a darkbrown solid (0.0297 g, 87%) that was used without further purification:mp 115-120° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.07 (d, J=9.7 Hz, 2H), 7.73(s, 1H), 7.32-7.23 (m, 4H), 6.77 (d, J=8.5 Hz, 2H), 3.85 (br, 2H); ESIMSm/z 336 (M⁺).

Example 47 Preparation of4-[5-(4-trifluoromethylphenyl)-4,5-dihydro-isoxazol-3-yl]-phenylamine

Step 1.{4-[5-(4-Trifluoromethylphenyl)-4,5-dihydro-isoxazol-3-yl]-phenyl}-carbamicacid tert-butyl ester. To a stirred solution of NCS (57 mg, 0.424 mmol)and pyridine (3 μL) in chloroform (1.7 mL) was added4-N-t-BOC-aminobenzaldehyde oxime (100 mg, 0.424 mmol). The reaction wasstirred at room temperature for 10 min. 4-Trifluoromethylstyrene (78 μL,0.53 mmol) was then added and the temperature was increased to 45° C. Tothis solution was added dropwise triethylamine (62 μL, 0.445 mmol)dissolved in chloroform (0.5 mL). The reaction was stirred at 45° C. for5 h. The cooled solution was diluted with chloroform (10 mL) and washedwith water (2×5 mL). The organic phase was then dried over MgSO₄,filtered and concentrated to give the isoxazoline (100 mg, 58%): ¹H NMR(400 MHz, CDCl₃) δ 7.40-7.83 (m, 8H), 6.60 (br s, 1H), 5.76 (dd, J=11.0,7.7 Hz, 1H), 3.81 (dd, J=16.5, 11.0 Hz, 1H), 3.29 (dd, J=16.5, 7.7 Hz,1H); EIMS m/z 406 (M⁺).

Step 2.4-[5-(4-Trifluoromethylphenyl)-4,5-dihydro-isoxazol-3-yl]-phenylamine.To a stirred solution of the N—BOC isoxazoline (prepared in step 1) inCH₂Cl₂ (2.5 mL) was added trifluoroacetic acid (6.16 mmol, 0.46 mL) andthe reaction was stirred at room temperature for 3 h. The solution wasconcentrated and the residue was taken up in saturated KHCO₃ solution (5mL) and stirred for 30 min. The mixture was then extracted with CH₂Cl₂(3×10 mL). The organic phase was dried over MgSO₄, filtered andconcentrated to afford the expected aniline (68 mg, 90%): ¹H NMR (400MHz, CDCl₃) δ 7.45-7.63 (m, 6H), 6.67 (d, J=8.6 Hz, 2H), 5.72 (dd,J=10.9, 7.6 Hz, 1H), 3.92 (br s, 2H), 3.78 (dd, J=16.7, 10.9 Hz, 1H),3.25 (dd, J=16.7, 7.6 Hz, 1H); EIMS m/z 306 (M⁺).

Example 48 Preparation of4-[3-(4-trifluoromethoxyphenyl)-4,5-dihydro-isoxazol-5-yl]-phenylamine

To a stirred solution of NCS (85 μL, 0.634 mmol) and pyridine (4 μL) inchloroform (2.5 mL) was added p-trifluoromethoxybenzaldehyde oxime (130mg, 0.634 mmol). The reaction was heated at 50° C. for 3 h.4-Aminostyrene (93 μL, 0.793 mmol) was then added followed by a solutionof triethylamine (93 μL, 0.666 mmol) dissolved in chloroform (0.5 mL)dropwise. The reaction was stirred at 50° C. for 3 h. The cooledsolution was diluted with chloroform (15 mL) and washed with water (2×10mL). The organic phase was then dried over MgSO₄, filtered andconcentrated. The residue was purified via radial chromatography using a2:1 hexane/EtOAc solution as the eluent (R_(f)=0.18) to afford4-[3-(4-trifluoromethoxyphenyl)-4,5-dihydro-isoxazol-5-yl]-phenylamine(125 mg; 61%): ¹H NMR (400 MHz, CDCl₃) δ 7.73 (d, J=8.2 Hz, 2H), 7.25(d, J=8.2 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 6.68 (d, J=8.2 Hz, 2H), 5.65(dd, J=10.9, 8.9 Hz, 1H), 3.55-3.75 (br s, 2H), 3.67 (dd, J=16.8, 10.9Hz, 1H), 3.30 (dd, J=16.8, 8.9 Hz, 1H); EIMS m/z 322 (M⁺).

Example 49 Preparation of1-(4-aminophenyl)-3-(4-trifluoromethoxyphenyl)-1,3-dihydroimidazol-2-one.These compounds were prepared according to the procedure described inBromidge et al. WO 2003057220 A1 with slight modifications.

Step 1. (2,2-Dimethoxyethyl)-(4-trifluoromethoxyphenyl)amine. To astirred solution of 4-trifluoromethoxyaniline (1 mL, 7.46 mmol) andglyoxaldehyde dimethyl acetal (60% v/v in water; 8.95 mmol, 1.6 mL) inEtOH (37 mL) was added 10% Pd/C (300 mg). The mixture was evacuated andflushed with nitrogen three times. Hydrogen was then added in a balloonapparatus and the mixture was stirred under 1 atm of hydrogen for 31 h.The mixture was filtered through a pad of Celite® and the pad was washedwith EtOH (25 mL). The ethanol was removed under reduced pressure andthe residue was diluted with CH₂Cl₂ (30 mL). The layers were separatedand the organic phase was dried over MgSO₄, filtered and concentrated togive (2,2-dimethoxyethyl)-(4-trifluoromethoxyphenyl)amine (1.7 g, 86%):¹H NMR (400 MHz, CDCl₃) δ 7.04 (d, J=8.9 Hz, 2H), 6.59 (d, J=8.9 Hz,2H), 4.56 (t, J=5.4 Hz, 1H), 3.92 (br s, 1H), 3.51 (d, J=5.4 Hz, 2H),3.42 (s, 6H); EIMS m/z 265 (M⁺).

Step 2.1-(2,2-Dimethoxyethyl)-3-(4-nitrophenyl)-1-(4-trifluoromethoxyphenyl)-urea.To a stirred solution of(2,2-dimethoxyethyl)-(4-trifluoromethoxyphenyl)amine (0.85 g, 3.2 mmol)dissolved in CH₂Cl₂ (32 mL) was added p-nitrophenyl isocyanate (0.58 g,3.53 mmol) and the reaction mixture was stirred at room temperatureovernight. The mixture was diluted with CH₂Cl₂ (50 mL) and was washedsuccessively with NaHCO₃ (30 mL) and brine (30 mL). The organic phasewas then dried over MgSO₄, filtered and concentrated. The residue waspurified via radial chromatography using a 2:1 hexane/EtOAc solution asthe eluent (R_(f)=0.32) to afford1-(2,2-dimethoxyethyl)-3-(4-nitrophenyl)-1-(4-trifluoromethoxyphenyl)-urea(0.87 g, 63%): ¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, J=9.2 Hz, 2H),7.50-7.30 (m, 6H), 7.02 (br s, 1H), 4.65 (t, J=5.4 Hz, 1H), 3.82 (d,J=5.4 Hz, 2H), 3.41 (s, 6H); EIMS m/z 429 (M⁺).

Step 3.1-(4-Nitrophenyl)-3-(4-trifluoromethoxyphenyl)-1,3-dihydroimidazol-2-one.To a stirred solution of1-(2,2-dimethoxyethyl)-3-(4-nitrophenyl)-1-(4-trifluoromethoxyphenyl)-urea(0.23 g, 0.53 mmol) dissolved in toluene (28 mL) was added concentratedHCl (2 drops). The reaction mixture was stirred at reflux for 3 h. Thecooled solution was diluted with EtOAc (75 mL) and washed with saturatedNaHCO₃ (25 mL) and brine (25 mL). The organic phase was then dried overMgSO₄, filtered and concentrated. The residue was purified via radialchromatography using a 2:1 hexane/EtOAc solution as the eluent(R_(f)=0.28) to afford1-(4-nitrophenyl)-3-(4-trifluoromethoxyphenyl)-1,3-dihydroimidazol-2-one(134 mg, 71%): ¹H NMR (400 MHz, CDCl₃) δ 8.35 (d, J=9.2 Hz, 2H), 7.93(d, J=9.2 Hz, 2H), 7.67 (d, J=9.2 Hz, 2H), 7.34 (d, J=9.2 Hz, 2H), 6.87(d, J=3.3 Hz, 1H), 6.81 (d, J=3.3 Hz, 1H); EIMS m/z 365 (M⁺).

Step 4.1-(4-Aminophenyl)-3-(4-trifluoromethoxyphenyl)-1,3-dihydro-imidazol-2-one.To a stirred solution of1-(4-nitrophenyl)-3-(4-trifluoromethoxyphenyl)-1,3-dihydroimidazol-2-one(120 mg, 0.33 mmol) in EtOAc (3.5 mL) was added tin dichloride (371 mg,1.64 mmol) and the reaction mixture was stirred at reflux for 3 h. Thecooled solution was poured onto ice (15 mL) and the pH was adjusted topH 7-8 by the addition of 10% NaHCO₃. The mixture was extracted withEtOAc (3×10 mL) and washed with brine (10 mL). The organic phase wasthen dried over MgSO₄, filtered and concentrated to obtain1-(4-aminophenyl)-3-(4-trifluoromethoxyphenyl)-1,3-dihydroimidazol-2-one(102 mg, 92%): ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, J=8.8 Hz, 2H), 7.37(d, J=8.8 Hz, 2H), 7.32 (d, J=8.8 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 6.69(d, J=3.3 Hz, 1H), 6.65 (d, J=3.3 Hz, 1H); EIMS m/z 335 (M⁺).

Example 50 Preparation of1-(4-aminophenyl)-3-(4-trifluoromethoxyphenyl)-imidazolidin-2-one

To a solution of1-(4-nitrophenyl)-3-(4-trifluoromethoxyphenyl)-1,3-dihydroimidazol-2-one(144 mg, 0.395 mmol) in EtOH (40 mL) was added 10% Pd/C (100 mg). Themixture was evacuated and flushed with nitrogen three times. The Parrvessel was pressurized to 45 psi of hydrogen and shaken for 5 h. Thedepressurized solution was filtered through a pad of Celite® and the padwas washed with EtOH (25 mL). The ethanol was removed under reducedpressure to afford the title product (114 mg, 95%): ¹H NMR (400 MHz,CDCl₃) δ 7.61 (d, J=9.2 Hz, 2H), 7.33 (d, J=9.2 Hz, 2H), 7.21 (d, J=8.6Hz, 2H), 6.71 (d, J=9.2 Hz, 2H), 3.92 (s, 4H), 3.61 (br s, 2H); EIMS m/z307 (M⁺).

Example 51 Preparation of4-[6-(4-trifluoromethoxyphenyl)-pyridazin-3-yl]-phenylamine

Step 1. 3-Chloro-6-(4-trifluoromethoxyphenyl)-pyridazine. To a solutioncontaining 3,6-dichloropyridazine (0.3 g, 2.01 mmol),4-trifluoromethoxyphenyl-boronic acid (0.50 g, 2.42 mmol) and 2 M K₂CO₃(2 mL, 4.03 mmol) dissolved in dry 1,4-dioxane (11 mL) was addeddichlorobis(triphenylphosphine)palladium(II) (14 mg, 0.02 mmol). Themixture was irradiated using a CEM Discover microwave at 190° C. for 30min. The mixture was diluted with ether (100 mL) and washed with brine(30 mL). The organic phase was then dried over MgSO₄, filtered andconcentrated. The residue was purified via radial chromatography using a3:1 hexane/EtOAc solution as the eluent. Two fractions were isolated.The first fraction (R_(f)=0.63) was shown to be the bis-Suzuki product(95 mg, 12%). The second fraction isolated (R_(f)=0.34) was identifiedas 3-chloro-6-(4-trifluoromethoxyphenyl)-pyridazine (174 mg, 32%): ¹HNMR (400 MHz, CDCl₃) δ 8.10 (d, J=9.2 Hz, 2H), 7.83 (d, J=8.9 Hz, 2H),7.60 (d, J=8.9 Hz, 2H), 7.37 (d, J=9.2 Hz, 2H); EIMS m/z 274 (M⁺).

Step 2. 4-[6-(4-Trifluoromethoxyphenyl)-pyridazin-3-yl]-phenylamine. Toa solution containing 3-chloro-6-(4-trifluoromethoxyphenyl)-pyridazine(157 mg, 0.57 mmol), 4-aminophenylboronic acid (118 mg, 0.86 mmol) and 2M K₂CO₃ (0.57 mL, 1.14 mmol) dissolved in dry 1,4-dioxane (3.5 mL) wasadded dichlorobis(triphenylphosphine)palladium(II) (4 mg, 0.006 mmol).The mixture was irradiated using a CEM Discover microwave at 190° C. for30 min. The mixture was diluted with ether (100 mL) and washed withbrine (30 mL). The organic phase was then dried over MgSO₄, filtered andconcentrated. The residue was purified via radial chromatography using a97:3 CHCl₃/CH₃OH solution as the eluent (R_(f)=0.26) to afford the titlecompound (105 mg, 56%): ¹H NMR (400 MHz, CDCl₃) δ 8.18 (d, J=8.6 Hz,2H), 8.01 (d, J=8.6 Hz, 2H), 7.30-7.45 (m, 4H), 6.82 (d, J=8.6 Hz, 2H),3.96 (br s, 2H); EIMS m/z 331 (M⁺).

Example 52 Preparation of4-[3-(4-trifluoromethoxyphenyl)-4,5-dihydro-[1,2,4]oxadiazol-5-yl]-benzaldehyde

The compound was prepared according to the general procedure ofSrivastava et al. J. Heterocycl. Chem. 1987, 24, 101 with slightmodifications. To a stirred solution of4-(trifluoromethoxy)benzamidoxime (Acros) (300 mg, 1.36 mmol) dissolvedin acetic acid (1.4 mL) was added 1,4-terephthaldehyde (1.1 g, 8.18mmol) and the reaction mixture was stirred at room temperature for 4 d.The mixture was then dissolved in CHCl₃ (20 mL) followed by addition ofheptane (10 mL). This solution was concentrated under reduced pressure.This procedure was repeated twice. The residue was purified via radialchromatography using a 99:1 CHCl₃/CH₃OH solution as the eluent. Twofractions were isolated. The first fraction isolated (R_(f)=0.30) wasshown to be starting material (20 mg). The second fraction isolated(R_(f)=0.17) was shown to be the title compound (23 mg, 5%): ¹H NMR (400MHz, CDCl₃) δ 10.02 (s, 1H), 7.91 (d, J=8.2 Hz, 2H), 7.77 (d, J=9.2 Hz,2H), 7.70 (d, J=8.2 Hz, 2H), 7.27 (d, J=8.2 Hz, 2H), 6.64 (d, J=4.3 Hz,1H), 5.18 (d, J=4.3 Hz, 1H); EIMS m/z 336 (M⁺).

Example 53 Preparation of4-[5-(4-trifluoromethoxyphenyl)-[1,2,4]oxadiazol-3-yl]phenylamine

Step 1.{4-[5-(4-Trifluoromethoxyphenyl)-[1,2,4]oxadiazol-3-yl]-phenyl}-carbamicacid tert-butyl ester. To a stirred solution oftert-butyl-4-(N-hydroxycarbamimidoyl)phenylcarbamate (Ace Synthesis)(500 mg, 1.99 mmol) dissolved in acetic acid (2.5 mL) was added4-trifluoromethoxybenzaldehyde (1.7 mL, 11.94 mmol), and the reactionmixture was stirred at room temperature for 4 d. The mixture was dilutedwith CHCl₃ (20 mL) and filtered through a pad of Celite®. The pad waswashed with CHCl₃ (20 mL). Heptane (20 mL) was then added to thesolution and the solution was concentrated under reduced pressure. Thisprocedure was repeated twice. The residue was purified via radialchromatography using a 3:1 hexane/EtOAc solution as the eluent. Twofractions were isolated. The first fraction isolated (R_(f)=0.42) wasshown to be the title compound (127 mg, 15%): ¹H NMR (300 MHz, CDCl₃) δ8.26 (d, J=8.9 Hz, 2H), 8.09 (d, J=8.9 Hz, 2H), 7.52 (d, J=8.6 Hz, 2H),7.39 (d, J=8.3 Hz, 2H), 6.70 (s, 1H), 1.54 (s, 9H); EIMS 421 (M⁺). Thesecond fraction isolated (R_(f)=0.11) was shown to be the4,5-dihydro-1,2,4-oxadiazole (96 mg; 11%). ¹H NMR (300 MHz, CDCl₃) δ8.40 (d, J=8.9 Hz, 2H), 8.00 (d, J=8.9 Hz, 2H), 7.51 (d, J=8.9 Hz, 2H),7.22-7.31 (m, 3H), 6.87 (s, 1H), 1.54 (s, 9H); EIMS m/z 423 (M⁺).

Step 2.4-[5-(4-Trifluoromethoxyphenyl)-[1,2,4]oxadiazol-3-yl]-phenylamine. To astirred solution of{4-[5-(4-trifluoromethoxyphenyl)-[1,2,4]oxadiazol-3-yl]-phenyl}-carbamicacid tert-butyl ester (198 mg, 0.47 mmol) in CH₂Cl₂ (4.7 mL) was addedtrifluoroacetic acid (11.76 mmol, 0.87 mL) and the reaction mixture wasstirred at room temperature for 3 h. The solution was concentrated andthe residue was taken up in saturated KHCO₃ solution (10 mL) and stirredfor 30 min. The mixture was then extracted with CH₂Cl₂ (3×10 mL). Theorganic phase was dried over MgSO₄, filtered and concentrated to afford4-[5-(4-trifluoromethoxyphenyl)-[1,2,4]oxadiazol-3-yl]-phenylamine (127mg; 84%): ¹H NMR (300 MHz, CDCl₃) δ 8.26 (d, J=8.9 Hz, 2H), 7.97 (d,J=8.9 Hz, 2H), 7.39 (d, J=8.6 Hz, 2H), 6.77 (d, J=8.6 Hz, 2H), 3.40-3.80(br s, 2H); EIMS m/z 321 (M⁺).

Example 54 Preparation of1-(4-aminophenyl)-4-(4-trifluoromethoxyphenyl)-piperazine-2,5-dione

Step 1. 4-Nitrophenylamino acetic acid, methyl ester. To a solution ofethyl bromoacetate (60 g, 0.36 mol) and 4-nitroaniline (5 g, 0.036 mol)in DMF (100 mL) was added NaHCO₃ (60 g, 0.71 mol) andtetra-n-butylammonium iodide (500 mg, cat). The solution was heated to90° C. for 16 h, and then it was cooled and poured onto water (300 mL).The resulting yellow solid was filtered and air-dried. Recrystallizationfrom MeOH furnished the methyl ester (5 g) as a light yellow solid: mp179-182° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.13 (d, J=8.4 Hz, 2H), 6.57 (d,J=8.4 Hz, 2H), 5.10 (s, 1H), 4.02 (s, 2H), 3.85 (s, 3H).

Step 2. [(2-Chloroacetyl)-(4-trifluoromethoxyphenyl)-amino]-acetic acidmethyl ester. To a suspension of 4-nitrophenylamino acetic acid methylester (3.0 g, 14.2 mmol) in toluene (30 mL) was added chloroacetylchloride (3 mL, excess). The solution was heated to 80° C. for 1 h,whereupon the solid dissolved. The solution was then cooled andconcentrated, and then the residual solid was recrystallized from MeOHto give the ester (3.5 g) as a light yellow solid: mp 106-109° C.; ¹HNMR (400 MHz, CDCl₃) δ 8.36 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.4 Hz, 2H),4.42 (s, 2H), 3.93 (s, 2H), 3.79 (s, 3H); MS m/z 286 (M⁺).

Step 3.1-(4-Aminophenyl)-4-(4-trifluoromethoxyphenyl)-piperazine-2,5-dione. Theproduct of step 2 (0.6 g, 2.3 mmol) was combined with4-trifluoromethoxyaniline (0.81 g, 4.6 mmol) and the materials wereheated to 140° C. for 90 min. The residual solid was stirred with CH₂Cl₂(50 mL) and filtered to remove the hydrochloride salt of the aniline,and then the residue was concentrated and purified. Chromatography(elution with EtOAc-hexanes) furnished the nitrophenyl piperazinedione(0.44 g) as a white solid, mp 223-224° C. Reduction of the nitro groupusing a Pd/C catalyst under conditions described above gave the titleamine as a white solid: mp 250° C. dec; ¹H NMR (400 MHz, CDCl₃) δ 7.4(d, J=8.5 Hz, 2H), 7.33 (d, J=8.6 Hz, 2H), 7.12 (d, J=8.7 Hz, 2H), 6.75(d, J=8.7 Hz, 2H), 4.5 (s, 2H), 4 45 (s, 2H); MS m/z 366.2 (M+H⁺).

Example 55 Preparation of5-(4-aminophenyl)-3-(4-trifluoromethylphenyl)-3H-[1,3,4]oxadiazol-2-one

5-(4-Nitrophenyl)-3-(4-trifluoromethylphenyl) 3H-[1,3,4]oxadiazole-2-onewas prepared by treating the corresponding 4-nitrobenzoic acidN′-(4-trifluoromethylphenyl)hydrazide with phosgene, using conditionsdescribed by Reimlinger et al. in Chem. Ber. 1970, 103, 1934. The nitrogroup was then reduced to the amine by treatment with hydrogen and Pd/Cin EtOH: mp 160-163° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.1 (d, J=8.4 Hz,2H), 7.75 (m, 4H), 6.75 (d, J=8.4 Hz, 2H), 4.1 (br s, 2H); MS m/z 322.6(MAI).

Example 56 Preparation of{4-[1-(4-pentafluoroethyloxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenyl}-carbamicacid tert-butyl ester (Compound 1)

A solution of4-[1-(4-pentafluoroethyloxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenylamine(1.0 g, 2.7 mmol) in dry THF (8 mL) was stirred while p-nitrophenylchloroformate (0.60 g, 3 mmol) was added in one portion and the solutionwas allowed to stir for 3 h. The resulting solid was filtered andair-dried. A smaller portion of the p-nitrophenylcarbamate (152 mg, 0.28mmol) was suspended in dry THF (3 mL). To this were added2-methyl-2-propanol (41 mg, 0.32 mmol) in dry THF (1 mL) followed by NaH(60% mineral oil dispersion; 26 mg, 0.67 mmol) in one portion.Additional dry THF (1 mL) was used to rinse joints, etc. The solutionwas heated to 60° C. (external) for 1.5 h, at which point TLC (3:3:3:1EtOAc/hexanes/CH₂Cl₂/acetone) showed no starting material. The mixturewas cooled and allowed to stir at 25° C. for 20 h. The mixture wascooled, poured on to ice-water (50 mL), and extracted with EtOAc (3×50mL). The combined extracts were washed with satd aq NaCl (75 mL), dried(Na₂SO₄), filtered and concentrated. RP-HPLC (acid-free mediumwater-acetonitrile gradient) provided the title compound (31 mg, 23%) asan off-white solid: mp 205-209° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.55 (s,1H), 8.12 (d, J=9.0 Hz, 2H), 7.80 (d, J=9.3 Hz, 2H), 7.48 (d, J=8.8 Hz,2H), 7.38 (d, J=9.0 Hz, 2H), 6.58 (s, 1H), 1.54 (s, 9H); ESIMS m/z 471(M+H), 469 (M−H). Compound 2 in Table 1 was synthesized as in Example56.

Example 57 Preparation of{4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenyl}-carbamicacid 1-(5-ethoxy-pyrimidin-2-yl)-1-methyl-ethyl ester (Compound 3)

4-[1-(4-Trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-benzoyl azide(204 mg, 0.55 mmol) was taken up in dry toluene (2 mL), and the mixturewas heated to 110° C. and stirred at that temperature for 1.5 h. Gasevolution was observed during the heating. The mixture was cooled, andthen the alcohol (106 mg, 0.59 mmol) and NaH (60% in mineral oildispersion; 76 mg, 1.9 mmol) were added. The mixture was stirred at 25°C. for 18 h. The mixture was poured onto H₂O (50 mL) and was extractedwith EtOAc (3×50 mL). The combined organic extracts were dried overNa₂SO₄, filtered and concentrated to give a light tan residue. Silicagel column chromatography (3:3:3:1 cyclohexane:EtOAc:CH₂Cl₂:acetone)gave the title compound (97 mg, 34%) as a light tan solid: mp 168-171°C.; ¹H NMR (400 MHz, CDCl₃) δ 8.52 (s, 1H), 8.37 (s, 2H), 8.08 (d, J=9.0Hz, 2H), 7.77 (d, J=8.9 Hz, 2H), 7.42 (d, J=8.7 Hz, 2H), 7.36 (d, J=9.0Hz, 2H), 6.91 (s, 1H), 4.12 (q, J=7.0 Hz, 2H), 1.87 (s, 6H), 1.44 (t,J=6.9 Hz, 3H); ESIMS m/z 529 (M+H), 527 (M−H); HRMS-ESI (m/z): [M]⁺calcdfor C₂₅H₂₃F₃N₆O₄, 528.1727; found, 528.1730. Compounds 4-8 in Table 1were synthesized as in Example 57.

Example 58 Preparation of{4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenyl}-carbamicacid 1-methyl-pentyl ester (Compound 9)

4-[1-(4-Trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-benzoyl azide(131 mg, 0.350 mmol) was suspended in dry toluene (1.0 mL). To theresulting slurry was added 2-hexanol (221 μL, 1.75 mmol) in one portion.The off-white slurry was then heated to 100° C. (external). Once HPLCanalysis indicated complete consumption of the starting material, theclear yellow solution was cooled to 23° C. and concentrated. Silica gelchromatography (Biotage 10 g SNAP column, eluted with a 20% to 40% to75% EtOAc/hexanes gradient) provided the title compound (134 mg, 85%) asa white solid: mp 111-113° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.54 (s, 1H),8.13 (d, J=8.8 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.51 (d, J=8.7 Hz, 2H),7.37 (dd, J=9.0, 0.8 Hz, 2H), 6.76 (s, 1H), 5.00-4.83 (m, 1H), 1.76-1.44(m, 2H), 1.44-1.31 (m, 4H), 1.29 (d, J=6.3 Hz, 3H), 0.91 (t, J=7.0 Hz,3H); ESIMS m/z 449 (M+H), 447 (M−H); HRMS-ESI (m/z): [M]⁺calcd forC₂₂H₂₃F₃N₄O₃, 448.172; found, 448.173.

Compound 10 in Table 1 was synthesized as in Example 58.

Example 59 Preparation of{4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenyl}-carbamicacid 1,1-dimethyl-2-phenyl-ethyl ester (Compound 11)

4-[1-(4-Trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-benzoyl azide(93 mg, 0.248 mmol) was suspended in dry toluene (0.71 mL). To theresulting slurry was added 2-methyl-1-phenyl-2-propanol (191 μL, 1.24mmol) in one portion. The off-white slurry was then heated to 100° C.(external). Once HPLC analysis indicated complete consumption of thestarting material, the yellow slurry was cooled to 23° C., filteredthrough a medium porosity frit, and concentrated. Silica gelchromatography (Biotage 10 g SNAP column, eluted with a 10% to 40% to75% EtOAc/hexanes gradient) provided the title compound (71 mg, 58%) asa white solid: mp 153-155° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.54 (s, 1H),8.14 (d, J=8.7 Hz, 2H), 7.79 (d, J=9.0 Hz, 2H), 7.50 (d, J=8.5 Hz, 2H),7.38 (d, J=8.6 Hz, 2H), 7.34-7.17 (m, 5H), 6.61 (s, 1H), 3.19 (s, 2H),1.53 (s, 6H); ESIMS m/z 497 (M+H), 495 (M−H); HRMS-ESI (m/z): [M]⁺calcdfor C₂₆H₂₃F₃N₄O₃, 496.172; found, 496.172.

Example 60 Preparation of{4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenyl}-carbamicacid 1,1-dimethyl-prop-2-ynyl ester (Compound 12)

2-Methyl-3-butyn-2-ol (48 μL, 0.44 mmol) was added to a solution oftriphosgene (42 mg, 0.14 mmol) and pyridine (38 μL, 0.47 mmol) in CH₂Cl₂(1.0 mL) at 23° C. Gas evolution was observed during addition of thealcohol, and a precipitate was observed to form. The resulting slurrywas stirred at 23° C. for 1 h. Stirring was ceased, the solid wasallowed to settle to the bottom of the flask, and the supernatant wasadded via cannula to a slurry of4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenylamine (100mg, 0.312 mmol) and pyridine (38 μL, 0.47 mmol) in CH₂Cl₂ (1.0 mL) at23° C. A thick precipitate was observed to form. At this point, TLCanalysis indicated some starting material remained, so an equivalentamount of triphosgene/pyridine/alcohol was combined as above, and theresulting supernatant was again added to the aniline mixture. Afterstirring for another 3 h at 23° C., the reaction mixture was dilutedwith 30% EtOAc/hexanes (10 mL), and a fine white precipitate wasfiltered on a coarse frit. The clear yellow filtrate was concentrated,and the resulting yellow oil was purified by silica gel chromatography(Biotage 10 g SNAP column, eluted with a 10% to 25% to 50% EtOAc/hexanesgradient) to provide the title compound (55 mg, 41%) as a white solid:mp 164-165° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.54 (s, 1H), 8.13 (d, J=8.7Hz, 2H), 7.79 (d, J=9.0 Hz, 2H), 7.53 (d, J=8.5 Hz, 2H), 7.38 (d, J=8.8Hz, 2H), 6.73 (s, 1H), 2.61 (s, 1H), 1.77 (s, 6H); ESIMS m/z 431 (M+H);HRMS-ESI (m/z): [M]⁺ calcd for C₂₁H₁₇F₃N₄O₃, 430.125; found, 430.126.

Example 61 Preparation of{4-[1-(4-trifluoromethylphenyl)-1H-[1,2,4]triazol-3-yl]-phenyl}-carbamicacid 1,1-dimethyl-prop-2-ynyl ester (Compound 13)

4-[1-(4-Trifluoromethylphenyl)-1H-[1,2,4]triazol-3-yl]-benzoyl azide(137 mg, 0.383 mmol) was suspended in dry toluene (1.5 mL). To theresulting slurry was added 2-methyl-3-butyn-2-ol (187 μL, 1.91 mmol)followed by Et₃N (264 μL, 1.91 mmol). The off-white slurry was thenheated to 100° C. (external). Once HPLC analysis indicated completeconsumption of the starting material, the yellow slurry was cooled to23° C. and poured into 50% EtOAc/hexanes. The off-white slurry was thenfiltered through a medium porosity frit and concentrated. Silica gelchromatography (Biotage 10 g SNAP column, eluted with a 10% to 40% to75% EtOAc/hexanes gradient) provided the title compound (20 mg, 13%) asa white solid: mp 187-189° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.64 (s, 1H),8.14 (d, J=8.7 Hz, 2H), 7.90 (d, J=8.4 Hz, 2H), 7.79 (d, J=8.6 Hz, 2H),7.53 (d, J=8.6 Hz, 2H), 6.76 (s, 1H), 2.61 (s, 1H), 1.77 (s, 6H); ESIMSm/z 415 (M+H), 413 (M−H); HRMS-ESI (m/z): [A]⁺calcd for C₂₁H₁₇F₃N₄O₂,414.130; found, 414.131.

Example 62 Preparation of{4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenyl}-carbamicacid cyano-dimethyl-methyl ester (Compound 14)

4-[1-(4-Trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-benzoyl azide(107 mg, 0.286 mmol) was suspended in dry toluene (1.0 mL). To theresulting slurry was added 2-cyano-2-propanol (78 μL, 0.858 mmol). Theoff-white slurry was then heated to 90° C. (external). Within 10 sec atthis temperature, the slurry became homogenous and vigorous gasevolution was observed. Precipitate was observed to form after another10 min at this temperature. Once HPLC analysis indicated completeconsumption of the starting material, the yellow slurry was cooled to23° C. and poured into hexanes. The off-white slurry was then filteredthrough a medium porosity frit and concentrated. Silica gelchromatography (Biotage 10 g SNAP column, eluted with a 20% to 40% to75% EtOAc/hexanes gradient) provided the title compound (7 mg, 6%) as alight yellow solid: mp 172-175° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.55 (s,1H), 8.16 (d, J=8.6 Hz, 2H), 7.79 (d, J=9.0 Hz, 2H), 7.52 (d, J=8.4 Hz,2H), 7.38 (d, J=8.7 Hz, 2H), 6.79 (s, 1H), 1.84 (s, 6H); ESIMS m/z 432(M+H), 430 (M−H).

Example 63 Preparation of 4{4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenyl}-carbamicacid 1-cyclopropyl-ethyl ester (Compound 15)

4-[1-(4-Trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-benzoyl azide(84 mg, 0.225 mmol) was suspended in dry toluene (0.65 mL). To theresulting slurry was added 1-cyclopropylethyl alcohol (109 μL, 1.12mmol). The off-white slurry was then heated to 90° C. (external). Within10 sec at this temperature, the slurry became homogenous and vigorousgas evolution was observed. After 1 h, the slightly cloudy yellowsolution was cooled to 23° C. and concentrated. Silica gelchromatography (Biotage 10 g SNAP column, eluted with a 10% to 25% to50% EtOAc/hexanes gradient) provided recovered starting material (20 mg,24%) as a white solid along with the title compound (67 mg, 69%) as awhite solid: mp 123-124° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.54 (s, 1H),8.13 (d, J=8.7 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.51 (d, J=8.6 Hz, 2H),7.37 (d, J=8.6 Hz, 2H), 6.85 (s, 1H), 4.34 (dq, J=12.7, 6.3 Hz, 1H),1.38 (d, J=6.3 Hz, 3H), 1.14-0.95 (m, 1H), 0.67-0.42 (m, 3H), 0.29 (ddd,J=7.6, 6.5, 3.8 Hz, 1H); ESIMS m/z 433 (M+H), 431 (M−H).

Example 64 Preparation of4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenyl}-carbamicacid 1-cyclohexyl-ethyl ester (Compound 16)

4-[1-(4-Trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-benzoyl azide(90 mg, 0.241 mmol) was suspended in dry toluene (0.70 mL). To theresulting slurry was added (1-cyclohexyl)ethyl alcohol (166 μL, 1.20mmol). The off-white slurry was then heated to 90° C. (external). Within10 sec at this temperature, the slurry became homogenous and vigorousgas evolution was observed. A small amount of precipitate was observedto form after another 10 min at this temperature. Once HPLC analysisindicated complete consumption of the starting material, the yellowslurry was cooled to 23° C. and poured into 25% EtOAc/hexanes. Theoff-white slurry was then filtered through a medium porosity frit andconcentrated. Silica gel chromatography (Biotage 10 g SNAP column,eluted with a 15% to 30% to 50% EtOAc/hexanes gradient) provided thetitle compound (98 mg, 86%) as a white solid: mp 146-148° C.; ¹H NMR(400 MHz, CDCl₃) δ 8.54 (s, 1H), 8.13 (d, J=8.7 Hz, 2H), 7.78 (d, J=9.0Hz, 2H), 7.52 (d, J=8.5 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 6.89 (s, 1H),4.76 (p, J=6.3 Hz, 1H), 2.13-1.61 (m, 4H), 1.49 (tdd, J=11.8, 6.1, 3.1Hz, 1H), 1.24 (d, J=6.4 Hz, 3H), 1.22-0.96 (m, 6H); ESIMS m/z 475 (M+H),473 (M−H). Compounds 17-22 in Table 1 were synthesized as in Example 64.

Example 65 Preparation of4-methyl-4-{4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenylcarbamoyloxy}-pent-2-ynoicacid ethyl ester (Compound 23)

4-[1-(4-Trifluoromethylphenyl)-1H-[1,2,4]triazol-3-yl]-phenyl}-carbamicacid 1,1-dimethylprop-2-ynyl ester (Compound 13; 11981077; 88 mg, 0.20mmol) was dissolved in dry THF (2.0 mL) and cooled to −78° C. n-BuLi(164 μL of a 2.5 M solution in hexanes, 0.410 mmol) was then addeddropwise. The mixture was stirred for another 20 min at −78° C., andthen ethyl chloroformate (24 μL, 0.25 mmol) was added in one portion.The mixture was stirred for another 30 min at −78° C. and was thenwarmed to 23° C. The mixture was quenched with half-saturated aqueousNH₄Cl and extracted with 50% EtOAc/hexanes. The combined organic layerswere then washed with brine, dried over Na₂SO₄, and concentrated. Silicagel chromatography (Biotage 10 g SNAP column, eluted with a 15% to 30%to 50% to 75% EtOAc/hexanes gradient) followed by recrystallization fromEt₂O/hexanes provided the title compound (10 mg, 10%) as a yellow solid:mp 183-188° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.57 (s, 1H), 8.27 (d, J=8.7Hz, 2H), 7.80 (d, J=9.1 Hz, 2H), 7.40 (app d, J=8.7 Hz, 4H), 4.99 (s,1H), 3.66 (q, J=7.1 Hz, 2H), 1.70 (s, 6H), 0.98 (t, J=7.1 Hz, 3H); ESIMSm/z 503 (M+H).

Example 66 Preparation of{4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]phenyl}-carbamicacid 2,2,3,3,3-pentafluoro-1-methyl-propyl ester (Compound 24)

4-[1-(4-Trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-benzoyl azide(77 mg, 0.206 mmol) was suspended in dry toluene (0.60 mL). To theresulting slurry was added 3,3,4,4,4-pentafluoro-2-butanol (120 μL, 1.03mmol). The off-white slurry was then heated to 90° C. (external). Within10 sec at this temperature, the slurry became homogenous and vigorousgas evolution was observed. A small amount of precipitate was observedto form after another 10 min at this temperature. Once HPLC analysisindicated complete consumption of the starting material, the yellowslurry was cooled to 23° C. and poured into 25% EtOAc/hexanes. Theoff-white slurry was filtered through a medium porosity frit andconcentrated to provide the title compound (80 mg, 76%) as an off-whitesolid: mp 171-173° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 10.33 (s, 1H), 9.38(s, 1H), 8.10-7.99 (m, 4H), 7.67-7.58 (m, 4H), 5.81-5.23 (m, 1H), 1.47(d, J=6.3 Hz, 3H); ESIMS m/z 511 (M+H), 509 (M−H); HRMS-ESI (m/z): [M]⁺calcd for C₂₀H₁₄F₈N₄O₃, 510.0933; found 510.0998. Compound 25 in Table 1was synthesized as in Example 66.

Example 67 Preparation of2-{4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenylcarbamoyloxy}-hexanoicacid ethyl ester (Compound 26)

4-[1-(4-Trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-benzoyl azide(90 mg, 0.241 mmol) was suspended in dry toluene (0.70 mL). Theoff-white slurry was then heated to 90° C. (external) and stirred for 30min. Within 10 sec at this temperature, the slurry became homogenous andvigorous gas evolution was observed. The slightly cloudy yellow solutionwas cooled to 23° C. and ethyl 2-hydroxycaproate (52 μL, 1.20 mmol) wasadded. The mixture was stirred at 23° C. for 15 h more, and was thenpoured into 25% EtOAc/hexanes. The off-white slurry was filtered througha medium porosity frit and concentrated. Silica gel chromatography(Biotage 10 g SNAP column, eluted with a 15% to 30% to 50 to 75%EtOAc/hexanes gradient) provided the title compound (10 mg, 8%) as awhite solid: mp 135-139° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.55 (s, 1H),8.14 (d, J=8.7 Hz, 2H), 7.79 (d, J=9.0 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H),7.38 (dd, J=9.0, 0.8 Hz, 2H), 6.97 (s, 1H), 5.08 (dd, J=7.2, 5.4 Hz,1H), 4.25 (q, J=7.1 Hz, 2H), 1.95-1.80 (m, 2H), 1.52-1.34 (m, 4H), 1.30(t, J=7.1 Hz, 3H), 0.93 (t, J=7.2 Hz, 3H); ESIMS 507 (M+H), 505 (M−H).

Example 68 Preparation of 1-(4-(trifluoromethyl)phenyl)ethyl4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)-phenylcarbamate(Compound 27)

4-(1-(4-(Trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)benzoyl azide(62.5 mg, 0.174 mmol) was suspended in dry toluene (0.498 mL). To theresulting slurry was added 1-(4-(trifluoromethyl)phenyl)ethyl alcohol(36.5 mg, 0.192 mmol). The off-white slurry was heated to 100° C.(external) for 18 h and then cooled to ambient temperature. The reactionmixture was directly applied to a silica gel column, and elution with a10% to 50% to 100% EtOAc/hexanes gradient provided the title compound(57.6 mg, 63%) as a white solid: mp 155.5-158.5° C.; ¹H NMR (400 MHz,CDCl₃) δ 8.62 (s, 1H), 8.15 (d, J=8.8 Hz, 2H), 7.90 (d, J=8.5 Hz, 2H),7.79 (d, J=8.5 Hz, 2H), 7.64 (d, J=8.2 Hz, 2H), 7.51 (app t, J=8.4 Hz,4H), 6.79 (s, 1H), 5.95 (q, J=6.6 Hz, 1H), 1.63 (d, J=6.7 Hz, 3H); ESIMS521 (M+H), 519 (M−H).

Example 69 Preparation of Carbamates—General Method A

The acyl azide was suspended in dry toluene (0.35 M). To the resultingslurry was added the appropriate alcohol (1.20 equiv). The slurry washeated to 100° C. (external) for 4-24 h and then cooled to ambienttemperature. The product was isolated by vacuum filtration or purifiedby silica gel column chromatography (after applying the materialdirectly to the column) eluting with EtOAc/hexanes gradient. In someinstances, further purification by recrystallization was necessary.Typical solvents used include: chloroform-d, diethyl ether/hexanes, anddiethyl ether/dichloromethane/hexanes mixtures. Compounds 28-121 inTable 1 were synthesized as in Example 69.

Example 70 Preparation of Carbamates—General Method B

The acyl azide was suspended in dry toluene (0.35 M). To the resultingslurry was added the appropriate alcohol (1.20 equiv). The slurry washeated to 100° C. (external) for 4-24 h and then cooled to ambienttemperature. Triethylamine (1.50 equiv) was added and the reactionmixture was stirred at ambient temperature for an additional 1 h. Theproduct was isolated by vacuum filtration or purified by silica gelcolumn chromatography (after applying the material directly to thecolumn) eluting with EtOAc/hexanes gradient. Compounds 122-129 weresynthesized as in Example 70.

Example 71 Preparation of 1-(6-(trifluoromethyl)pyridin-3-yl)ethylethyl(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)carbamate(Compound 130)

1-(6-(Trifluoromethyl)pyridin-3-yl)ethyl4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenylcarbamate(54 mg, 0.10 mmol) was dissolved in anhydrous DMF (0.5 mL) under N₂ andcooled to 0° C. NaH (60% suspension in mineral oil; 4.4 mg, 0.11 mmol)was added, and the mixture was stirred for 10 min at 0° C. Iodoethane (9μL, 0.11 mmol) was added, and the mixture was warmed to ambienttemperature and stirred for 1 h. Additional NaH (4 mg) and iodoethane (5μL) were added at ambient temperature to promote complete consumption ofthe starting material. The mixture was quenched with aqueous NH₄Cl andextracted with 80% EtOAc/hexanes (×3). The combined organic layers werewashed with brine, dried over Na₂SO₄, and concentrated. The crudeproduct was applied to a silica gel column, and elution with a 15% to40% to 80% EtOAc/hexanes gradient provided the title compound (52.1 mg,91%) as a light yellow oil: IR 3111, 2983, 2936, 1707, 1519, 1340, 1268,1155 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.62 (s, J=10.6 Hz, 1H), 8.58 (s,1H), 8.21 (d, J=8.5 Hz, 2H), 7.81 (d, J=9.0 Hz, 2H), 7.73-7.58 (m, 2H),7.40 (d, J=8.5 Hz, 2H), 7.30 (d, J=8.5 Hz, 2H), 5.95 (q, J=6.6 Hz, 1H),3.84-3.70 (m, 2H), 1.53 (d, J=6.2 Hz, 3H), 1.19 (t, J=7.1 Hz, 3H);HRMS-FAB (m/z) [M+H]⁺ calcd for C₂₆H₂₁F₆N₅O₃, 565.1549; found, 565.1568.

Example 72 Preparation of tert-butylmethyl(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)carbamate(Compound 131)

tert-Butyl(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)carbamate(120 mg, 0.286 mmol) was dissolved in anhydrous DMF (2.0 mL) under N₂and cooled to 0° C. NaH (60% suspension in mineral oil; 15 mg, 0.372mmol) was added, and the mixture was stirred for 10 min at 0° C.Iodomethane (23 μL, 0.372 mmol) was added, and the mixture was warmed toambient temperature and stirred for 1 h. The mixture was quenched withaqueous NH₄Cl and extracted with 80% EtOAc/hexanes (×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄, andconcentrated. The crude product was applied to a silica gel column, andelution with a 15% to 40% to 80% EtOAc/hexanes gradient provided thetitle compound (108.0 mg, 87%) as a white solid: mp 125-128° C.; ¹H NMR(400 MHz, CDCl₃) δ 8.55 (s, 1H), 8.14 (d, J=8.6 Hz, 2H), 7.79 (d, J=8.9Hz, 2H), 7.38 (d, J=9.8 Hz, 2H), 7.35 (d, J=8.8 Hz, 2H), 3.31 (s, 3H),1.47 (s, 9H); HRMS-FAB (m/z) [M+H]⁺ calcd for C₂₁H₂₁F₃N₄O₃, 434.156;found, 434.157.

Example 73 Preparation of O-methyl4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenylcarbamothioate(Compound 132)

Step 1. 4-(1-(4-(Trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)anilinewas dissolved in THF (2.5 mL) to give a tan solution. Phenylchlorothionoformate (0.205 mg, 1.19 mmol) was then added. A solidprecipitated immediately and stirring became difficult. Additional THF(2.5 mL) was added to facilitate stirring. An additional portion ofphenyl chlorothionoformate (0.205 mg, 1.19 mmol) was added followed bytriethylamine (0.38 mL, 2.80 mmol). The reaction was quenched with satdaq NaHCO₃ and extracted with 50% EtOAc/hexanes. The organic layer waswashed with aq NaHCO₃ solution and brine, dried over Na₂SO₄, andconcentrated. Purification via silica gel chromatography (15% to 30% to50% to 80% EtOAc/hexanes gradient) affordedN,N-bis(thionophenoxy)-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline(0.472 g, 80%) as a yellow solid: mp 142-144° C.; ¹H NMR (400 MHz,CDCl₃) δ 8.58 (s, 1H), 8.34 (d, J=8.6 Hz, 2H), 7.80 (d, J=9.0 Hz, 2H),7.66 (d, J=8.6 Hz, 2H), 7.49-7.34 (m, 6H), 7.34-7.28 (m, 2H), 7.26-7.13(m, 4H); HRMS-FAB (m/z) [M+H]⁺ calcd for C₂₉H₁₉F₃N₄O₃S₂, 592.085; found,592.0861.

Step 2. To a solution of the product from Step 1 in MeOH (2.5 mL) andTHF (2.5 mL) was added NaOH (2.5 mL of a 1 M aq solution). A thickyellow precipitate formed immediately. Additional THF, MeOH, and 1 MNaOH (2.5 mL each) were added and a clear yellow solution was obtained.The mixture was then poured into aq NaHCO₃ and extracted with 50%EtOAc/hexanes (×3). The combined organic layers were washed with brine,dried over Na₂SO₄, and concentrated to give a yellow solid. The solidwas triturated with 20% EtOAc/hexanes to give the title compound (137mg, 51%) as a white solid. The filtrate was concentrated and purified bysilica gel chromatography (eluting with 15% to 40% to 80% EtOAc/hexanesgradient) to afford additional product (57.6 mg, 0.126 mmol, 22%): mp192-194° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 11.32 (s, 1H), 9.39 (s, 1H),8.14-7.95 (m, 4H), 7.90-7.65 (br, 1H), 7.62 (app dd, J=9.0, 0.7 Hz, 2H),7.60-7.40 (br, 1H), 4.01 (br s, 3H); HRMS-FAB (m/z) [M+H]⁺ calcd forC₁₇H₁₃F₃N₄O₂S, 394.071; found, 394.0712.

Example 74 Preparation of O-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenylcarbamothioate(Compound 133)

Under a N₂ atmosphere, thiophosgene (0.56 mmol) was added dropwise tocold dichloromethane cooled in an ice bath. To this solution was added acold 0.2 mM (0.13 mmol) K₂CO₃ solution. The reaction was stirred for 10min. 4-(1-(4-(Trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline(0.56 mmol) was dissolved in dichloromethane and added dropwise to theabove mixture. The reaction was allowed to stir for another 10 min. Acold 0.6 mM (0.92 mmol) KOH solution was then added. After 30 min, thereaction mixture was diluted with dichloromethane and washed with waterand brine. The organic layer was dried over MgSO₄ and concentrated. Thecrude isothiocyanate was used without further purification in the nextstep.

To a slurry of NaH (9.2 mg of a 60% suspension in mineral oil, 0.229mmol) in THF (1 mL) at 0° C. was added1-(6-(trifluoromethyl)pyridine-3-yl)ethanol (43.7 mg, 0.229 mmol) inPhCH₃ (0.4 mL). The mixture was warmed to ambient temperature andstirred for 15 min, and then the isothiocyanate from above (75.6 mg,0.209 mmol) in THF (1 mL) was added via cannula. After stirring for 20min, the mixture was quenched by addition of aq NH₄Cl solution andextracted with EtOAc (X₃). The combined organic extracts were washedwith brine, dried over Na₂SO₄, and concentrated. The crude product wasapplied to a silica gel column, and elution with a 15% to 40% to 65%EtOAc/hexanes gradient provided the title compound (88.2 mg, 77%) as anoff-white solid: mp 186.5-188° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.76 (s,1H), 8.58 (s, 1H), 8.50 (s, 1H), 8.19 (d, J=8.7 Hz, 2H), 7.91-7.83 (m,1H), 7.80 (d, J=9.1 Hz, 2H), 7.69 (d, J=8.1 Hz, 1H), 7.49-7.29 (m, 4H),6.68 (q, J=6.7 Hz, 1H), 1.76 (d, J=6.6 Hz, 3H); HRMS-FAB (m/z) [M+H]⁺calcd for C₂₄H₁₇F₆N₅O₂S, 553.101; found, 553.1006.

Example 75 Preparation of O-4-fluorophenyl4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenylcarbamothioate(Compound 134)

Into a 25 mL round-bottomed flask were added4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline (200 mg,0.624 mmol), O-4-fluorophenyl carbonochloridothioate (238 mg, 1.249mmol), and triethylamine (0.348 mL, 2.498 mmol) in THF (5 mL). Thesolution was stirred under ambient conditions for 2 h before the solventwas removed under reduced pressure. The crude product was added to asilica gel column and was eluted with EtOAc/hexanes gradient to affordthe title compound (50 mg, 0.105 mmol, 17%) as a yellow solid: mp164-169° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 9.42 (s, 1H), 8.19-8.04 (m,6H), 7.97 (br s, 1H), 7.66-7.57 (d, J=8.24 Hz, 2H), 7.33-7.19 (m, 4H);ESIMS m/z 475 (M+1).

Example 76 Preparation of methyl4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenylcarbamate(Compound 135)

4-Nitrophenyl4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenylcarbamate(1.90 g, 3.55 mmol) was slurried in MeOH (15 mL) and cooled in a −10° C.dry ice/acetone bath. Sodium methoxide (1.33 mL of a 30 wt % solution inMeOH, 7.10 mmol) was added dropwise over 10 min. The resulting brightyellow slurry was warmed to ambient temperature and poured into icewater (150 mL). After stirring vigorously for 10 min, the mixture wasfiltered on a Büchner funnel. The tan solid was rinsed with water anddried in air. Recrystallization from MeOH/water provided the titlecompound (0.989 g, 65%) as a tan solid: mp 183-184.5° C.; ¹H NMR (300MHz, CDCl₃) δ 8.55 (s, 1H), 8.14 (d, J=8.7 Hz, 2H), 7.79 (d, J=9.0 Hz,2H), 7.50 (d, J=8.6 Hz, 2H), 7.38 (d, J=8.9 Hz, 2H), 6.79 (s, 1H), 3.80(s, 3H); HRMS-FAB (m/z) [M+H]⁺ calcd for C₁₈H₁₃F₅N₄O₃, 428.0908; found,428.0903.

Example 77 Preparation ofmethyl-{4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenyl}-carbamicacid 4-nitrophenyl ester (Compound 136)

A suspension of4-[1-(4-trifluoroethyloxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenylamine(1.2 g, 3.7 mmol) in EtOH (4 mL) was treated with 1H-benzotriazole (0.48g, 4.0 mmol) and formaldehyde (0.5 mL of 37% aqueous, 6 mmol), and thesolution was heated to 40° C. for 10 min. Upon cooling, a solid formed,which was collected by filtration. There was obtained 1.33 g of thetriazole adduct as a light yellow solid, mp 185-187° C. This material(1.2 g, 2.66 mmol) was dissolved in THF (20 mL) and treated with NaBH₄(0.11 g, 2.9 mmol). The solution was stirred at ambient temperature for30 min, then heated to reflux for 1 h. After cooling, the solution waspoured onto water (30 mL) and extracted with ether. Drying andconcentration, followed by silica gel chromatography (75:25Hexanes:EtOAc) furnishedmethyl-{4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenyl}-amine(0.76 g, 86%) as a white solid, mp 121-123° C.; ¹H NMR (300 MHz, CDCl₃)δ 8.51 (s, 1H), 8.02 (d, J=8.8 Hz, 2H), 7.78 (d, J=9.1 Hz, 2H), 7.37 (d,J=8.3 Hz, 2H), 6.68 (d, J=8.8 Hz, 2H), 3.96 (s, 1H), 2.91 (s, 3H); EIMSm/z 499 (M⁺). A portion of this amine (0.11 g, 0.33 mmol) was dissolvedin dry THF (2 mL) and treated with 4-nitrophenyl chloroformate (0.069 g,0.34 mmol). The solid which formed over 10 min was collected byfiltration and air-dried to give an off-white solid (0.10 g): mp145-147° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.59 (s, 1H), 8.28 (d, J=8 Hz,4H), 7.8 (d, J=8 Hz, 2H), 7.50-7.3 (m, 6H) 3.55 (s, 3H); EIMS m/z 499(M⁺).

The compounds were tested against beet armyworm and corn earworm usingprocedures described in the following examples and reported in Table 2.

In each case of Table 2, the rating scale is as follows:

% Control (or Mortality) Rating 50-100 A Less than 50 B Not tested C

Example 78 Insecticidal Test for Beet Armyworm (Spodoptera exigua)

Bioassays on beet armyworm (BAW; Spodoptera exigua: Lepidoptera) wereconducted using a 128-well diet tray assay. Three to five second instarBAW larvae were placed in each well (3 mL) of the diet tray that hadbeen previously filled with 1 mL of artificial diet to which 50 μg/cm²of the test compound (dissolved in 50 μL of 90:10 acetone-water mixture)had been applied (to each of eight wells) and then allowed to dry. Trayswere covered with a clear self-adhesive cover, and held at 25° C., 14:10light-dark for six days. Percent mortality was recorded for the larvaein each well; activity in the eight wells was then averaged. The resultsfor both bioassays are indicated in Table 2.

Example 79 Insecticidal Test for Corn Earworm (Helicoverpa zea)

Bioassays on corn earworm (CEW; Helicoverpa zea: Lepidoptera) wereconducted using a 128-well diet tray assay. Three to five second instarCEW larvae were placed in each well (3 mL) of the diet tray that hadbeen previously filled with 1 mL of artificial diet to which 50 μg/cm²of the test compound (dissolved in 50 μL of 90:10 acetone-water mixture)had been applied (to each of eight wells) and then allowed to dry. Trayswere covered with a clear self-adhesive cover, and held at 25° C., 14:10light-dark for six days. Percent mortality was recorded for the larvaein each well; activity in the eight wells was then averaged. The resultsfor both bioassays are indicated in Table 2.

The compounds were also tested against green peach aphid using aprocedure described in the following example and reported in Table 2.

In each case of Table 2, the rating scale is as follows:

% Control (or Mortality) Rating 80-100 A Less than 80 B Not tested C

Example 80 Insecticidal Test for Green Peach Aphid (Myzus persicae) inFoliar Spray Assay

Cabbage seedlings grown in 3-inch pots, with 2-3 small (3-5 cm) trueleaves, were used as test substrate. The seedlings were infested with20-50 green peach aphids (wingless adult and nymph) one day prior tochemical application. Four pots with individual seedlings were used foreach treatment. Compounds (2 mg) were dissolved in 2 mL ofacetone/methanol (1:1) solvent, forming stock solutions of 1000 ppm. Thestock solutions were diluted 5× with 0.025% Tween 20 in H₂O to obtainthe solution at 200 ppm. A hand-held Devilbiss sprayer was used forspraying a solution to both sides of cabbage leaves until runoff.Reference plants (solvent check) were sprayed with the diluent only.Treated plants were held in a holding room for three days atapproximately 25° C. and 40% relative humidity (RH) prior to grading.Evaluation was conducted by counting the number of live aphids per plantunder a microscope. Insecticidal activity was measured by using Abbott'scorrection formula are presented in Table 2:

Corrected % Control=100*(X−Y)/X

where

-   -   X=No. of live aphids on solvent check plants    -   Y=No. of live aphids on treated plants

Acid and Salt Derivatives and Solvates

The compounds disclosed in this invention can be in the form ofpesticidally acceptable acid addition salts.

By way of non-limiting example, an amine function can form salts withhydrochloric, hydrobromic, sulfuric, phosphoric, acetic, benzoic,citric, malonic, salicylic, malic, fumaric, oxalic, succinic, tartaric,lactic, gluconic, ascorbic, maleic, aspartic, benzenesulfonic,methanesulfonic, ethanesulfonic, hydroxymethanesulfonic, andhydroxyethanesulfonic acids.

Additionally, by way of non-limiting example, an acid function can formsalts including those derived from alkali or alkaline earth metals andthose derived from ammonia and amines. Examples of preferred cationsinclude sodium, potassium, magnesium, and aminium cations.

The salts are prepared by contacting the free base form with asufficient amount of the desired acid to produce a salt. The free baseforms may be regenerated by treating the salt with a suitable diluteaqueous base solution such as dilute aqueous NaOH, potassium carbonate,ammonia, and sodium bicarbonate. As an example, in many cases, apesticide is modified to a more water soluble form e.g.2,4-dichlorophenoxy acetic acid dimethyl amine salt is a more watersoluble form of 2,4-dichlorophenoxy acetic acid, a well known herbicide.

The compounds disclosed in this invention can also form stable complexeswith solvent molecules that remain intact after the non-complexedsolvent molecules are removed from the compounds. These complexes areoften referred to as “solvates”.

Stereoisomers

Certain compounds disclosed in this document can exist as one or morestereoisomers. The various stereoisomers include geometric isomers,diastereomers, and enantiomers. Thus, the compounds disclosed in thisinvention include racemic mixtures, individual stereoisomers, andoptically active mixtures. It will be appreciated by those skilled inthe art that one stereoisomer may be more active than the others.Individual stereoisomers and optically active mixtures may be obtainedby selective synthetic procedures, by conventional synthetic proceduresusing resolved starting materials, or by conventional resolutionprocedures.

Pests

In another embodiment, the invention disclosed in this document can beused to control pests.

In another embodiment, the invention disclosed in this document can beused to control pests of the Phylum Nematoda.

In another embodiment, the invention disclosed in this document can beused to control pests of the Phylum Arthropoda.

In another embodiment, the invention disclosed in this document can beused to control pests of the Subphylum Chelicerata.

In another embodiment, the invention disclosed in this document can beused to control pests of the Class Arachnida.

In another embodiment, the invention disclosed in this document can beused to control pests of the Subphylum Myriapoda.

In another embodiment, the invention disclosed in this document can beused to control pests of the Class Symphyla.

In another embodiment, the invention disclosed in this document can beused to control pests of the Subphylum Hexapoda.

In another embodiment, the invention disclosed in this document can beused to control pests of the Class Insecta.

In another embodiment, the invention disclosed in this document can beused to control Coleoptera (beetles). A non-exhaustive list of thesepests includes, but is not limited to, Acanthoscelides spp. (weevils),Acanthoscelides obtectus (common bean weevil), Agrilus planipennis(emerald ash borer), Agriotes spp. (wireworms), Anoplophora glabripennis(Asian longhorned beetle), Anthonomus spp. (weevils), Anthonomus grandis(boll weevil), Aphidius spp., Apion spp. (weevils), Apogonia spp.(grubs), Ataenius spretulus (Black Turgrass Ataenius), Atomaria linearis(pygmy mangold beetle), Aulacophore spp., Bothynoderes punctiventris(beet root weevil), Bruchus spp. (weevils), Bruchus pisorum (peaweevil), Cacoesia spp., Callosobruchus maculatus (southern cow peaweevil), Carpophilus hemipteras (dried fruit beetle), Cassida vittata,Cerosterna spp., Cerotoma spp. (chrysomeids), Cerotoma trifurcata (beanleaf beetle), Ceutorhynchus spp. (weevils), Ceutorhynchus assimilis(cabbage seedpod weevil), Ceutorhynchus napi (cabbage curculio),Chaetocnema spp. (chrysomelids), Colaspis spp. (soil beetles), Conoderusscalaris, Conoderus stigmosus, Conotrachelus nenuphar (plum curculio),Cotinus nitidis (Green June beetle), Crioceris asparagi (asparagusbeetle), Cryptolestes ferrugineus (rusty grain beetle), Cryptolestespusillus (flat grain beetle), Cryptolestes turcicus (Turkish grainbeetle), Ctenicera spp. (wireworms), Curculio spp. (weevils),Cyclocephala spp. (grubs), Cylindrocpturus adspersus (sunflower stemweevil), Deporaus marginatus (mango leaf-cutting weevil), Dermesteslardarius (larder beetle), Dermestes maculates (hide beetle), Diabroticaspp. (chrysolemids), Epilachna varivestis (Mexican bean beetle),Faustinus cubae, Hylobius pales (pales weevil), Hypera spp. (weevils),Hypera postica (alfalfa weevil), Hyperdoes spp. (Hyperodes weevil),Hypothenemus hampei (coffee berry beetle), Ips spp. (engravers),Lasioderma serricorne (cigarette beetle), Leptinotarsa decemlineata(Colorado potato beetle), Liogenys fuscus, Liogenys suturalis,Lissorhoptrus oryzophilus (rice water weevil), Lyctus spp. (woodbeetles/powder post beetles), Maecolaspis joliveti, Megascelis spp.,Melanotus communis, Meligethes spp., Meligethes aeneus (blossom beetle),Melolontha melolontha (common European cockchafer), Oberea brevis,Oberea linearis, Oryctes rhinoceros (date palm beetle), Oryzaephilusmercator (merchant grain beetle), Oryzaephilus surinamensis (sawtoothedgrain beetle), Otiorhynchus spp. (weevils), Oulema melanopus (cerealleaf beetle), Oulema oryzae, Pantomorus spp. (weevils), Phyllophaga spp.(May/June beetle), Phyllophaga cuyabana, Phyllotreta spp.(chrysomelids), Phynchites spp., Popillia japonica (Japanese beetle),Prostephanus truncates (larger grain borer), Rhizopertha dominica(lesser grain borer), Rhizotrogus spp. (European chafer), Rhynchophorusspp. (weevils), Scolytus spp. (wood beetles), Shenophorus spp.(Billbug), Sitona lineatus (pea leaf weevil), Sitophilus spp. (grainweevils), Sitophilus granaries (granary weevil), Sitophilus oryzae (riceweevil), Stegobium paniceum (drugstore beetle), Tribolium spp. (flourbeetles), Tribolium castaneum (red flour beetle), Tribolium confusum(confused flour beetle), Trogoderma variabile (warehouse beetle), andZabrus tenebioides.

In another embodiment, the invention disclosed in this document can beused to control Dermaptera (earwigs).

In another embodiment, the invention disclosed in this document can beused to control Dictyoptera (cockroaches). A non-exhaustive list ofthese pests includes, but is not limited to, Blattella germanica (Germancockroach), Blatta orientalis (oriental cockroach), Parcoblattapennylvanica, Periplaneta americana (American cockroach), Periplanetaaustraloasiae (Australian cockroach), Periplaneta brunnea (browncockroach), Periplaneta fuliginosa (smokybrown cockroach), Pyncoselussuninamensis (Surinam cockroach), and Supella longipalpa (brownbandedcockroach).

In another embodiment, the invention disclosed in this document can beused to control Diptera (true flies). A non-exhaustive list of thesepests includes, but is not limited to, Aedes spp. (mosquitoes), Agromyzafrontella (alfalfa blotch leafminer), Agromyza spp. (leaf miner flies),Anastrepha spp. (fruit flies), Anastrepha suspensa (Caribbean fruitfly), Anopheles spp. (mosquitoes), Batrocera spp. (fruit flies),Bactrocera cucurbitae (melon fly), Bactrocera dorsalis (oriental fruitfly), Ceratitis spp. (fruit flies), Ceratitis capitata (Mediterraneafruit fly), Chrysops spp. (deer flies), Cochliomyia spp. (screwworms),Contarinia spp. (gall midges), Culex spp. (mosquitoes), Dasineura spp.(gall midges), Dasineura brassicae (cabbage gall midge), Delia spp.,Delia platura (seedcorn maggot), Drosophila spp. (vinegar flies), Fanniaspp. (filth flies), Fannia canicularis (little house fly), Fanniascalaris (latrine fly), Gasterophilus intestinalis (horse bot fly),Gracillia perseae, Haematobia irritans (horn fly), Hylemyia spp. (rootmaggots), Hypoderma lineatum (common cattle grub), Liriomyza spp.(leafminer flies), Liriomyza brassica (serpentine leafminer), Melophagusovinus (sheep ked), Musca spp. (muscid flies), Musca autumnalis (facefly), Musca domestica (house fly), Oestrus ovis (sheep bot fly),Oscinella frit (frit fly), Pegomyia betae (beet leafminer), Phorbiaspp., Psila rosae (carrot rust fly), Rhagoletis cerasi (cherry fruitfly), Rhagoletis pomonella (apple maggot), Sitodiplosis mosellana(orange wheat blossom midge), Stomoxys calcitrans (stable fly), Tabanusspp. (horse flies), and Tipula spp. (crane flies).

In another embodiment, the invention disclosed in this document can beused to control Hemiptera (true bugs). A non-exhaustive list of thesepests includes, but is not limited to, Acrosternum hilare (green stinkbug), Blissus leucopterus (chinch bug), Calocoris norvegicus (potatomirid), Cimex hemipterus (tropical bed bug), Cimex lectularius (bedbug), Dagbertus fasciatus, Dichelops furcatus, Dysdercus suturellus(cotton stainer), Edessa meditabunda, Eurygaster maura (cereal bug),Euschistus heros, Euschistus servus (brown stink bug), Helopeltisantonii, Helopeltis theivora (tea blight plantbug), Lagynotomus spp.(stink bugs), Leptocorisa oratorius, Leptocorisa varicornis, Lygus spp.(plant bugs), Lygus hesperus (western tarnished plant bug),Maconellicoccus hirsutus, Neurocolpus longirostris, Nezara viridula(southern green stink bug), Phytocoris spp. (plant bugs), Phytocoriscalifornicus, Phytocoris relativus, Piezodorus guildingi, Poecilocapsuslineatus (fourlined plant bug), Psallus vaccinicola, Pseudacystaperseae, Scaptocoris castanea, and Triatoma spp. (bloodsucking conenosebugs/kissing bugs).

In another embodiment, the invention disclosed in this document can beused to control Homoptera (aphids, scales, whiteflies, leafhoppers). Anon-exhaustive list of these pests includes, but is not limited to,Acrythosiphon pisum (pea aphid), Adelges spp. (adelgids), Aleurodesproletella (cabbage whitefly), Aleurodicus disperses, Aleurothrixusfloccosus (woolly whitefly), Aluacaspis spp., Amrasca bigutellabigutella, Aphrophora spp. (leafhoppers), Aonidiella aurantii(California red scale), Aphis spp. (aphids), Aphis gossypii (cottonaphid), Aphis pomi (apple aphid), Aulacorthum solani (foxglove aphid),Bemisia spp. (whiteflies), Bemisia argentifolii, Bemisia tabaci(sweetpotato whitefly), Brachycolus noxius (Russian aphid),Brachycorynella asparagi (asparagus aphid), Brevennia rehi, Brevicorynebrassicae (cabbage aphid), Ceroplastes spp. (scales), Ceroplastes rubens(red wax scale), Chionaspis spp. (scales), Chrysomphalus spp. (scales),Coccus spp. (scales), Dysaphis plantaginea (rosy apple aphid), Empoascaspp. (leafhoppers), Eriosoma lanigerum (woolly apple aphid), Iceryapurchasi (cottony cushion scale), Idioscopus nitidulus (mangoleafhopper), Laodelphax striatellus (smaller brown planthopper),Lepidosaphes spp., Macrosiphum spp., Macrosiphum euphorbiae (potatoaphid), Macrosiphum granarium (English grain aphid), Macrosiphum rosae(rose aphid), Macrosteles quadrilineatus (aster leafhopper), Mahanarvafrimbiolata, Metopolophium dirhodum (rose grain aphid), Mictislongicornis, Myzus persicae (green peach aphid), Nephotettix spp.(leafhoppers), Nephotettix cinctipes (green leafhopper), Nilaparvatalugens (brown planthopper), Parlatoria pergandii (chaff scale),Parlatoria ziziphi (ebony scale), Peregrinus maidis (corn delphacid),Philaenus spp. (spittlebugs), Phylloxera vitifoliae (grape phylloxera),Physokermes piceae (spruce bud scale), Planococcus spp. (mealybugs),Pseudococcus spp. (mealybugs), Pseudococcus brevipes (pine applemealybug), Quadraspidiotus perniciosus (San Jose scale), Rhapalosiphumspp. (aphids), Rhapalosiphum maida (corn leaf aphid), Rhapalosiphum padi(oat bird-cherry aphid), Saissetia spp. (scales), Saissetia oleae (blackscale), Schizaphis graminum (greenbug), Sitobion avenae (English grainaphid), Sogatella furcifera (white-backed planthopper), Therioaphis spp.(aphids), Toumeyella spp. (scales), Toxoptera spp. (aphids),Trialeurodes spp. (whiteflies), Trialeurodes vaporariorum (greenhousewhitefly), Trialeurodes abutiloneus (bandedwing whitefly), Unaspis spp.(scales), Unaspis yanonensis (arrowhead scale), and Zulia entreriana.

In another embodiment, the invention disclosed in this document can beused to control Hymenoptera (ants, wasps, and bees). A non-exhaustivelist of these pests includes, but is not limited to, Acromyrrmex spp.,Athalia rosae, Atta spp. (leafcutting ants), Camponotus spp. (carpenterants), Diprion spp. (sawflies), Formica spp. (ants), Iridomyrmex humilis(Argentine ant), Monomorium ssp., Monomorium minumum (little black ant),Monomorium pharaonis (Pharaoh ant), Neodiprion spp. (sawflies),Pogonomyrmex spp. (harvester ants), Polistes spp. (paper wasps),Solenopsis spp. (fire ants), Tapoinoma sessile (odorous house ant),Tetranomorium spp. (pavement ants), Vespula spp. (yellow jackets), andXylocopa spp. (carpenter bees).

In another embodiment, the invention disclosed in this document can beused to control Isoptera (termites). A non-exhaustive list of thesepests includes, but is not limited to, Coptotermes spp., Coptotermescurvignathus, Coptotermes frenchii, Coptotermes formosanus (Formosansubterranean termite), Cornitermes spp. (nasute termites), Cryptotermesspp. (drywood termites), Heterotermes spp. (desert subterraneantermites), Heterotermes aureus, Kalotermes spp. (drywood termites),Incistitermes spp. (drywood termites), Macrotermes spp. (fungus growingtermites), Marginitermes spp. (drywood termites), Microcerotermes spp.(harvester termites), Microtermes obesi, Procornitermes spp.,Reticulitermes spp. (subterranean termites), Reticulitermes banyulensis,Reticulitermes grassei, Reticulitermes flavipes (eastern subterraneantermite), Reticulitermes hageni, Reticulitermes hesperus (westernsubterranean termite), Reticulitermes santonensis, Reticulitermessperatus, Reticulitermes tibialis, Reticulitermes virginicus,Schedorhinotermes spp., and Zootermopsis spp. (rotten-wood termites).

In another embodiment, the invention disclosed in this document can beused to control Lepidoptera (moths and butterflies). A non-exhaustivelist of these pests includes, but is not limited to, Achoea janata,Adoxophyes spp., Adoxophyes orana, Agrotis spp. (cutworms), Agrotisipsilon (black cutworm), Alabama argillacea (cotton leafworm), Amorbiacuneana, Amyelosis transitella (navel orangeworm), Anacamptodesdefectaria, Anarsia lineatella (peach twig borer), Anomis sabulifera(jute looper), Anticarsia gemmatalis (velvetbean caterpillar), Archipsargyrospila (fruit tree leafroller), Archips rosana (rose leaf roller),Argyrotaenia spp. (tortricid moths), Argyrotaenia citrana (orangetortrix), Autographa gamma, Bonagota cranaodes, Borbo cinnara (rice leaffolder), Bucculatrix thurberiella (cotton leaf perforator), Caloptiliaspp. (leaf miners), Capua reticulana, Carposina niponensis (peach fruitmoth), Chilo spp., Chlumetia transversa (mango shoot borer),Choristoneura rosaceana (oblique banded leaf roller), Chrysodeixis spp.,Cnaphalocerus medinalis (grass leafroller), Colias spp., Conpomorphacramerella, Cossus cossus (carpenter moth), Crambus spp. (Sod webworms),Cydia funebrana (plum fruit moth), Cydia molesta (oriental fruit moth),Cydia nignicana (pea moth), Cydia pomonella (codling moth), Darnadiducta, Diaphania spp. (stem borers), Diatraea spp. (stalk borers),Diatraea saccharalis (sugarcane borer), Diatraea graniosella(southwestern corn borer), Earias spp. (bollworms), Earias insulata(Egyptian bollworm), Earias vitella (rough northern bollworm),Ecdytopopha aurantianum, Elasmopalpus lignosellus (lesser cornstalkborer), Epiphysias postruttana (light brown apple moth), Ephestia spp.(flour moths), Ephestia cautella (almond moth), Ephestia elutella(tobacco moth), Ephestia kuehniella (Mediterranean flour moth), Epimecesspp., Epinotia aporema, Erionota thrax (banana skipper), Eupoeciliaambiguella (grape berry moth), Euxoa auxiliaris (army cutworm), Feltiaspp. (cutworms), Gortyna spp. (stemborers), Grapholita molesta (orientalfruit moth), Hedylepta indicata (bean leaf webber), Helicoverpa spp.(noctuid moths), Helicoverpa armigera (cotton bollworm), Helicoverpa zea(bollworm/corn earworm), Heliothis spp. (noctuid moths), Heliothisvirescens (tobacco budworm), Hellula undalis (cabbage webworm),Indarbela spp. (root borers), Keiferia lycopersicella (tomato pinworm),Leucinodes orbonalis (eggplant fruit borer), Leucoptera malifoliella,Lithocollectis spp., Lobesia botrana (grape fruit moth), Loxagrotis spp.(noctuid moths), Loxagrotis albicosta (western bean cutworm), Lymantriadispar (gypsy moth), Lyonetia clerkella (apple leaf miner), Mahasenacorbetti (oil palm bagworm), Malacosoma spp. (tent caterpillars),Mamestra brassicae (cabbage armyworm), Maruca testulalis (bean podborer), Metisa plana (bagworm), Mythimna unipuncta (true armyworm),Neoleucinodes elegantalis (small tomato borer), Nymphula depunctalis(rice caseworm), Operophthera brumata (winter moth), Ostrinia nubilalis(European corn borer), Oxydia vesulia, Pandemis cerasana (common curranttortrix), Pandemis heparana (brown apple tortrix), Papilio demodocus,Pectinophora gossypiella (pink bollworm), Peridroma spp. (cutworms),Peridroma saucia (variegated cutworm), Perileucoptera coffeella (whitecoffee leafminer), Phthorimaea operculella (potato tuber moth),Phyllocnisitis citrella, Phyllonorycter spp. (leafminers), Pieris rapae(imported cabbageworm), Plathypena scabs, Plodia interpunctella (Indianmeal moth), Plutella xylostella (diamondback moth), Polychrosis viteana(grape berry moth), Prays endocarps, Prays oleae (olive moth),Pseudaletia spp. (noctuid moths), Pseudaletia unipunctata (armyworm),Pseudoplusia includens (soybean looper), Rachiplusia nu, Scirpophagaincertulas, Sesamia spp. (stemborers), Sesamia inferens (pink rice stemborer), Sesamia nonagrioides, Setora nitens, Sitotroga cerealella(Angoumois grain moth), Sparganothis pilleriana, Spodoptera spp.(armyworms), Spodoptera exigua (beet armyworm), Spodoptera frugiperda(fall armyworm), Spodoptera oridania (southern armyworm), Synanthedonspp. (root borers), Thecla basilides, Thermisia gemmatalis, Tineolabisselliella (webbing clothes moth), Trichoplusia ni (cabbage looper),Tuta absoluta, Yponomeuta spp., Zeuzera coffeae (red branch borer), andZeuzera pyrina (leopard moth).

In another embodiment, the invention disclosed in this document can beused to control Mallophaga (chewing lice). A non-exhaustive list ofthese pests includes, but is not limited to, Bovicola ovis (sheep bitinglouse), Menacanthus stramineus (chicken body louse), and Menopongallinea (common hen louse).

In another embodiment, the invention disclosed in this document can beused to control Orthoptera (grasshoppers, locusts, and crickets). Anon-exhaustive list of these pests includes, but is not limited to,Anabrus simplex (Mormon cricket), Gryllotalpidae (mole crickets),Locusta migratoria, Melanoplus spp. (grasshoppers), Microcentrumretinerve (angular winged katydid), Pterophylla spp. (katydids),chistocerca gregaria, Scudderia furcata (fork tailed bush katydid), andValanga nigricorni.

In another embodiment, the invention disclosed in this document can beused to control Phthiraptera (sucking lice). A non-exhaustive list ofthese pests includes, but is not limited to, Haematopinus spp. (cattleand hog lice), Linognathus ovillus (sheep louse), Pediculus humanuscapitis (human body louse), Pediculus humanus humanus (human body lice),and Pthirus pubis (crab louse),

In another embodiment, the invention disclosed in this document can beused to control Siphonaptera (fleas). A non-exhaustive list of thesepests includes, but is not limited to, Ctenocephalides canis (dog flea),Ctenocephalides felis (cat flea), and Pulex irritans (human flea).

In another embodiment, the invention disclosed in this document can beused to control Thysanoptera (thrips). A non-exhaustive list of thesepests includes, but is not limited to, Frankliniella fusca (tobaccothrips), Frankliniella occidentalis (western flower thrips),Frankliniella shultzei Frankliniella williamsi (corn thrips),Heliothrips haemorrhaidalis (greenhouse thrips), Riphiphorothripscruentatus, Scirtothrips spp., Scirtothrips citri (citrus thrips),Scirtothrips dorsalis (yellow tea thrips), Taeniothripsrhopalantennalis, and Thrips spp.

In another embodiment, the invention disclosed in this document can beused to control Thysanura (bristletails). A non-exhaustive list of thesepests includes, but is not limited to, Lepisma spp. (silverfish) andThermobia spp. (firebrats).

In another embodiment, the invention disclosed in this document can beused to control Acarina (mites and ticks). A non-exhaustive list ofthese pests includes, but is not limited to, Acarapsis woodi (trachealmite of honeybees), Acarus spp. (food mites), Acarus siro (grain mite),Aceria mangiferae (mango bud mite), Aculops spp., Aculops lycopersici(tomato russet mite), Aculops pelekasi, Aculus pelekassi, Aculusschlechtendali (apple rust mite), Amblyomma americanum (lone star tick),Boophilus spp. (ticks), Brevipalpus obovatus (privet mite), Brevipalpusphoenicis (red and black flat mite), Demodex spp. (mange mites),Dermacentor spp. (hard ticks), Dermacentor variabilis (American dogtick), Dermatophagoides pteronyssinus (house dust mite), Eotetranycusspp., Eotetranychus carpini (yellow spider mite), Epitimerus spp.,Eriophyes spp., Ixodes spp. (ticks), Metatetranycus spp., Notoedrescati, Oligonychus spp., Oligonychus coffee, Oligonychus ilicus (southernred mite), Panonychus spp., Panonychus citri (citrus red mite),Panonychus ulmi (European red mite), Phyllocoptruta oleivora (citrusrust mite), Polyphagotarsonemun latus (broad mite), Rhipicephalussanguineus (brown dog tick), Rhizoglyphus spp. (bulb mites), Sarcoptesscabiei (itch mite), Tegolophus perseaflorae, Tetranychus spp.,Tetranychus urticae (two-spotted spider mite), and Varroa destructor(honey bee mite).

In another embodiment, the invention disclosed in this document can beused to control Nematoda (nematodes). A non-exhaustive list of thesepests includes, but is not limited to, Aphelenchoides spp. (bud and leaf& pine wood nematodes), Belonolaimus spp. (sting nematodes),Criconemella spp. (ring nematodes), Dirofilaria immitis (dog heartworm),Ditylenchus spp. (stem and bulb nematodes), Heterodera spp. (cystnematodes), Heterodera zeae (corn cyst nematode), Hirschmanniella spp.(root nematodes), Hoplolaimus spp. (lance nematodes), Meloidogyne spp.(root knot nematodes), Meloidogyne incognita (root knot nematode),Onchocerca volvulus (hook-tail worm), Pratylenchus spp. (lesionnematodes), Radopholus spp. (burrowing nematodes), and Rotylenchusreniformis (kidney-shaped nematode).

In another embodiment, the invention disclosed in this document can beused to control Symphyla (symphylans). A non-exhaustive list of thesepests includes, but is not limited to, Scutigerella immaculata.

For more detailed information consult “HANDBOOK OF PEST CONTROL—THEBEHAVIOR, LIFE HISTORY, AND CONTROL OF HOUSEHOLD PESTS” by ArnoldMallis, 9th Edition, copyright 2004 by GIE Media Inc.

Mixtures

The invention disclosed in this document can also be used with variousinsecticides, both for reasons of economy and synergy. Such insecticidesinclude, but are not limited to, antibiotic insecticides, macrocycliclactone insecticides (for example, avermectin insecticides, milbemycininsecticides, and spinosyn insecticides), arsenical insecticides,botanical insecticides, carbamate insecticides (for example,benzofuranyl methylcarbamate insecticides, dimethylcarbamateinsecticides, oxime carbamate insecticides, and phenyl methylcarbamateinsecticides), diamide insecticides, desiccant insecticides,dinitrophenol insecticides, fluorine insecticides, formamidineinsecticides, fumigant insecticides, inorganic insecticides, insectgrowth regulators (for example, chitin synthesis inhibitors, juvenilehormone mimics, juvenile hormones, moulting hormone agonists, moultinghormones, moulting inhibitors, precocenes, and other unclassified insectgrowth regulators), nereistoxin analogue insecticides, nicotinoidinsecticides (for example, nitroguanidine insecticides, nitromethyleneinsecticides, and pyridylmethylamine insecticides), organochlorineinsecticides, organophosphorus insecticides, oxadiazine insecticides,oxadiazolone insecticides, phthalimide insecticides, pyrazoleinsecticides, pyrethroid insecticides, pyrimidinamine insecticides,pyrrole insecticides, tetramic acid insecticides, tetronic acidinsecticides, thiazole insecticides, thiazolidine insecticides, thioureainsecticides, urea insecticides, as well as, other unclassifiedinsecticides.

Some of the particular insecticides that can be employed beneficially incombination with the invention disclosed in this document include, butare not limited to, the following 1,2-dichloropropane,1,3-dichloropropene, abamectin, acephate, acetamiprid, acethion,acetoprole, acrinathrin, acrylonitrile, alanycarb, aldicarb, aldoxycarb,aldrin, allethrin, allosamidin, allyxycarb, alpha-cypermethrin,alpha-endosulfan, amidithion, aminocarb, amiton, amitraz, anabasine,athidathion, azadirachtin, azamethiphos, azinphos-ethyl,azinphos-methyl, azothoate, barium hexafluorosilicate, barthrin,bendiocarb, benfuracarb, bensultap, beta-cyfluthrin, beta-cypermethrin,bifenthrin, bioallethrin, bioethanomethrin, biopermethrin,bioresmethrin, bistrifluoron, borax, boric acid, boric acid,bromfenvinfos, bromocyclen, bromo-DDT, bromophos, bromophos-ethyl,bufencarb, buprofezin, butacarb, butathiofos, butocarboxim, butonate,butoxycarboxim, cadusafos, calcium arsenate, calcium polysulfide,camphechlor, carbanolate, carbaryl, carbofuran, carbon disulfide, carbontetrachloride, carbophenothion, carbosulfan, cartap,chlorantraniliprole, chlorbicyclen, chlordane, chlordecone,chlordimeform, chlorethoxyfos, chlorfenapyr, chlorfenvinphos,chlorfluazuron, chlormephos, chloroform, chloropicrin, chlorphoxim,chlorprazophos, chlorpyrifos, chlorpyrifos-methyl, chlorthiophos,chromafenozide, cinerin I, cinerin II, cismethrin, cloethocarb,closantel, clothianidin, copper acetoarsenite, copper arsenate, coppernaphthenate, copper oleate, coumaphos, coumithoate, crotamiton,crotoxyphos, crufomate, cryolite, cyanofenphos, cyanophos, cyanthoate,cyantraniliprole, cyclethrin, cycloprothrin, cyfluthrin, cyhalothrin,cypermethrin, cyphenothrin, cyromazine, cythioate, DDT, decarbofuran,deltamethrin, demephion, demephion-O, demephion-S, demeton,demeton-methyl, demeton-O, demeton-O-methyl, demeton-S,demeton-S-methyl, demeton-S-methylsulphon, diafenthiuron, dialifos,diatomaceous earth, diazinon, dicapthon, dichlofenthion, dichlorvos,dicresyl, dicrotophos, dicyclanil, dieldrin, diflubenzuron, dilor,dimefluthrin, dimefox, dimetan, dimethoate, dimethrin, dimethylvinphos,dimetilan, dinex, dinoprop, dinosam, dinotefuran, diofenolan,dioxabenzofos, dioxacarb, dioxathion, disulfoton, dithicrofos,d-limonene, DNOC, doramectin, ecdysterone, emamectin, EMPC, empenthrin,endosulfan, endothion, endrin, EPN, epofenonane, eprinomectin,esfenvalerate, etaphos, ethiofencarb, ethion, ethiprole, ethoate-methyl,ethoprophos, ethyl formate, ethyl-DDD, ethylene dibromide, ethylenedichloride, ethylene oxide, etofenprox, etrimfos, EXD, famphur,fenamiphos, fenazaflor, fenchlorphos, fenethacarb, fenfluthrin,fenitrothion, fenobucarb, fenoxacrim, fenoxycarb, fenpirithrin,fenpropathrin, fensulfothion, fenthion, fenthion-ethyl, fenvalerate,fipronil, flonicamid, flubendiamide, flucofuron, flucycloxuron,flucythrinate, flufenerim, flufenoxuron, flufenprox, fluvalinate,fonofos, formetanate, formothion, formparanate, fosmethilan, fospirate,fosthietan, furathiocarb, furethrin, gamma-cyhalothrin, gamma-HCH,halfenprox, halofenozide, HCH, HEOD, heptachlor, heptenophos,heterophos, hexaflumuron, HHDN, hydramethylnon, hydrogen cyanide,hydroprene, hyquincarb, imidacloprid, imiprothrin, indoxacarb,iodomethane, IPSP, isazofos, isobenzan, isocarbophos, isodrin,isofenphos, isoprocarb, isoprothiolane, isothioate, isoxathion,ivermectin, jasmolin I, jasmolin II, jodfenphos, juvenile hormone I,juvenile hormone II, juvenile hormone III, kelevan, kinoprene,lambda-cyhalothrin, lead arsenate, lepimectin, leptophos, lindane,lirimfos, lufenuron, lythidathion, malathion, malonoben, mazidox,mecarbam, mecarphon, menazon, mephosfolan, mercurous chloride,mesulfenfos, metaflumizone, methacrifos, methamidophos, methidathion,methiocarb, methocrotophos, methomyl, methoprene, methoxychlor,methoxyfenozide, methyl bromide, methylchloroform, methylene chloride,metofluthrin, metolcarb, metoxadiazone, mevinphos, mexacarbate,milbemectin, milbemycin oxime, mipafox, mirex, monocrotophos,morphothion, moxidectin, naftalofos, naled, naphthalene, nicotine,nifluridide, nitenpyram, nithiazine, nitrilacarb, novaluron,noviflumuron, omethoate, oxamyl, oxydemeton-methyl, oxydeprofos,oxydisulfoton, para-dichlorobenzene, parathion, parathion-methyl,penfluoron, pentachlorophenol, permethrin, phenkapton, phenothrin,phenthoate, phorate, phosalone, phosfolan, phosmet, phosnichlor,phosphamidon, phosphine, phoxim, phoxim-methyl, pirimetaphos,pirimicarb, pirimiphos-ethyl, pirimiphos-methyl, potassium arsenite,potassium thiocyanate, pp′-DDT, prallethrin, precocene I, precocene II,precocene III, primidophos, profenofos, profluthrin, promacyl,promecarb, propaphos, propetamphos, propoxur, prothidathion, prothiofos,prothoate, protrifenbute, pyraclofos, pyrafluprole, pyrazophos,pyresmethrin, pyrethrin I, pyrethrin II, pyridaben, pyridalyl,pyridaphenthion, pyrifluquinazon, pyrimidifen, pyrimitate, pyriprole,pyriproxyfen, quassia, quinalphos, quinalphos-methyl, quinothion,rafoxanide, resmethrin, rotenone, ryania, sabadilla, schradan,selamectin, silafluofen, silica gel, sodium arsenite, sodium fluoride,sodium hexafluorosilicate, sodium thiocyanate, sophamide, spinetoram,spinosad, spiromesifen, spirotetramat, sulcofuron, sulfoxaflor,sulfluramid, sulfotep, sulfuryl fluoride, sulprofos, tau-fluvalinate,tazimcarb, TDE, tebufenozide, tebufenpyrad, tebupirimfos, teflubenzuron,tefluthrin, temephos, TEPP, terallethrin, terbufos, tetrachloroethane,tetrachlorvinphos, tetramethrin, theta-cypermethrin, thiacloprid,thiamethoxam, thicrofos, thiocarboxime, thiocyclam, thiodicarb,thiofanox, thiometon, thiosultap, thuringiensin, tolfenpyrad,tralomethrin, transfluthrin, transpermethrin, triarathene, triazamate,triazophos, trichlorfon, trichlormetaphos-3, trichloronat, trifenofos,triflumuron, trimethacarb, triprene, vamidothion, vaniliprole, XMC,xylylcarb, zeta-cypermethrin, zolaprofos, and a-ecdysone.

Additionally, any combination of the above insecticides can be used.

The invention disclosed in this document can also be used, for reasonsof economy and synergy, with acaricides, algicides, antifeedants,avicides, bactericides, bird repellents, chemosterilants, fungicides,herbicide safeners, herbicides, insect attractants, insect repellents,mammal repellents, mating disrupters, molluscicides, plant activators,plant growth regulators, rodenticides, synergists, defoliants,desiccants, disinfectants, semiochemicals, and virucides (thesecategories not necessarily mutually exclusive).

For more information consult “COMPENDIUM OF PESTICIDE COMMON NAMES”located at http://www.alanwood.net/pesticides/index.html. Also consult“THE PESTICIDE MANUAL” 14th Edition, edited by C D S Tomlin, copyright2006 by British Crop Production Council.

Synergistic Mixtures

The invention disclosed in this document can be used with othercompounds such as the ones mentioned under the heading “Mixtures” toform synergistic mixtures where the mode of action of the compounds inthe mixtures are the same, similar, or different.

Examples of mode of actions include, but are not limited to:acetylcholinesterase inhibitor; sodium channel modulator; chitinbiosynthesis inhibitor; GABA-gated chloride channel antagonist; GABA andglutamate-gated chloride channel agonist; acetylcholine receptoragonist; MET I inhibitor; Mg-stimulated ATPase inhibitor; nicotinicacetylcholine receptor; Midgut membrane disrupter; oxidativephosphorylation disrupter, and ryanodine receptor (RyRs).

Additionally, the following compounds are known as synergists and can beused with the invention disclosed in this document: piperonyl butoxide,piprotal, propyl isome, sesamex, sesamolin, and sulfoxide.

Formulations

A pesticide is rarely suitable for application in its pure form. It isusually necessary to add other substances so that the pesticide can beused at the required concentration and in an appropriate form,permitting ease of application, handling, transportation, storage, andmaximum pesticide activity. Thus, pesticides are formulated into, forexample, baits, concentrated emulsions, dusts, emulsifiableconcentrates, fumigants, gels, granules, microencapsulations, seedtreatments, suspension concentrates, suspoemulsions, tablets, watersoluble liquids, water dispersible granules or dry flowables, wettablepowders, and ultra low volume solutions.

For further information on formulation types see “CATALOGUE OF PESTICIDEFORMULATION TYPES AND INTERNATIONAL CODING SYSTEM” Technical Monographn° 2, 5th Edition by CropLife International (2002).

Pesticides are applied most often as aqueous suspensions or emulsionsprepared from concentrated formulations of such pesticides. Suchwater-soluble, water-suspendable, or emulsifiable formulations, areeither solids, usually known as wettable powders, or water dispersiblegranules, or liquids usually known as emulsifiable concentrates, oraqueous suspensions. Wettable powders, which may be compacted to formwater dispersible granules, comprise an intimate mixture of thepesticide, a carrier, and surfactants. The concentration of thepesticide is usually from about 10% to about 90% by weight. The carrieris usually chosen from among the attapulgite clays, the montmorilloniteclays, the diatomaceous earths, or the purified silicates. Effectivesurfactants, comprising from about 0.5% to about 10% of the wettablepowder, are found among sulfonated lignins, condensednaphthalenesulfonates, naphthalenesulfonates, alkylbenzenesulfonates,alkyl sulfates, and non-ionic surfactants such as ethylene oxide adductsof alkyl phenols.

Emulsifiable concentrates of pesticides comprise a convenientconcentration of a pesticide, such as from about 50 to about 500 gramsper liter of liquid dissolved in a carrier that is either a watermiscible solvent or a mixture of water-immiscible organic solvent andemulsifiers. Useful organic solvents include aromatics, especiallyxylenes and petroleum fractions, especially the high-boilingnaphthalenic and olefinic portions of petroleum such as heavy aromaticnaphtha. Other organic solvents may also be used, such as the terpenicsolvents including rosin derivatives, aliphatic ketones such ascyclohexanone, and complex alcohols such as 2-ethoxyethanol. Suitableemulsifiers for emulsifiable concentrates are chosen from conventionalanionic and non-ionic surfactants.

Aqueous suspensions comprise suspensions of water-insoluble pesticidesdispersed in an aqueous carrier at a concentration in the range fromabout 5% to about 50% by weight. Suspensions are prepared by finelygrinding the pesticide and vigorously mixing it into a carrier comprisedof water and surfactants. Ingredients, such as inorganic salts andsynthetic or natural gums, may also be added, to increase the densityand viscosity of the aqueous carrier. It is often most effective togrind and mix the pesticide at the same time by preparing the aqueousmixture and homogenizing it in an implement such as a sand mill, ballmill, or piston-type homogenizer.

Pesticides may also be applied as granular compositions that areparticularly useful for applications to the soil. Granular compositionsusually contain from about 0.5% to about 10% by weight of the pesticide,dispersed in a carrier that comprises clay or a similar substance. Suchcompositions are usually prepared by dissolving the pesticide in asuitable solvent and applying it to a granular carrier which has beenpre-formed to the appropriate particle size, in the range of from about0.5 to about 3 mm. Such compositions may also be formulated by making adough or paste of the carrier and compound and crushing and drying toobtain the desired granular particle size.

Dusts containing a pesticide are prepared by intimately mixing thepesticide in powdered form with a suitable dusty agricultural carrier,such as kaolin clay, ground volcanic rock, and the like. Dusts cansuitably contain from about 1% to about 10% of the pesticide. They canbe applied as a seed dressing or as a foliage application with a dustblower machine.

It is equally practical to apply a pesticide in the form of a solutionin an appropriate organic solvent, usually petroleum oil, such as thespray oils, which are widely used in agricultural chemistry.

Pesticides can also be applied in the form of an aerosol composition. Insuch compositions the pesticide is dissolved or dispersed in a carrier,which is a pressure-generating propellant mixture. The aerosolcomposition is packaged in a container from which the mixture isdispensed through an atomizing valve.

Pesticide baits are formed when the pesticide is mixed with food or anattractant or both. When the pests eat the bait they also consume thepesticide. Baits may take the form of granules, gels, flowable powders,liquids, or solids. They are used in pest harborages.

Fumigants are pesticides that have a relatively high vapor pressure andhence can exist as a gas in sufficient concentrations to kill pests insoil or enclosed spaces. The toxicity of the fumigant is proportional toits concentration and the exposure time. They are characterized by agood capacity for diffusion and act by penetrating the pest'srespiratory system or being absorbed through the pest's cuticle.Fumigants are applied to control stored product pests under gas proofsheets, in gas sealed rooms or buildings or in special chambers.

Pesticides can be microencapsulated by suspending the pesticideparticles or droplets in plastic polymers of various types. By alteringthe chemistry of the polymer or by changing factors in the processing,microcapsules can be formed of various sizes, solubility, wallthicknesses, and degrees of penetrability. These factors govern thespeed with which the active ingredient within is released, which inturn, affects the residual performance, speed of action, and odor of theproduct.

Oil solution concentrates are made by dissolving pesticide in a solventthat will hold the pesticide in solution. Oil solutions of a pesticideusually provide faster knockdown and kill of pests than otherformulations due to the solvents themselves having pesticidal action andthe dissolution of the waxy covering of the integument increasing thespeed of uptake of the pesticide. Other advantages of oil solutionsinclude better storage stability, better penetration of crevices, andbetter adhesion to greasy surfaces.

Another embodiment is an oil-in-water emulsion, wherein the emulsioncomprises oily globules which are each provided with a lamellar liquidcrystal coating and are dispersed in an aqueous phase, wherein each oilyglobule comprises at least one compound which is agriculturally active,and is individually coated with a monolamellar or oligolamellar layercomprising: (1) at least one non-ionic lipophilic surface-active agent,(2) at least one non-ionic hydrophilic surface-active agent and (3) atleast one ionic surface-active agent, wherein the globules having a meanparticle diameter of less than 800 nanometers. Further information onthe embodiment is disclosed in U.S. patent publication 20070027034published Feb. 1, 2007, having patent application Ser. No. 11/495,228.For ease of use this embodiment will be referred to as “OIWE”.

For further information consult “INSECT PEST MANAGEMENT” 2nd Edition byD. Dent, copyright CAB International (2000). Additionally, for moredetailed information consult “HANDBOOK OF PEST CONTROL—THE BEHAVIOR,LIFE HISTORY, AND CONTROL OF HOUSEHOLD PESTS” by Arnold Mallis, 9thEdition, copyright 2004 by GIE Media Inc.

Other Formulation Components

Generally, the invention disclosed in this document when used in aformulation, such formulation can also contain other components. Thesecomponents include, but are not limited to, (this is a non-exhaustiveand non-mutually exclusive list) wetters, spreaders, stickers,penetrants, buffers, sequestering agents, drift reduction agents,compatibility agents, anti-foam agents, cleaning agents, andemulsifiers. A few components are described forthwith.

A wetting agent is a substance that when added to a liquid increases thespreading or penetration power of the liquid by reducing the interfacialtension between the liquid and the surface on which it is spreading.Wetting agents are used for two main functions in agrochemicalformulations: during processing and manufacture to increase the rate ofwetting of powders in water to make concentrates for soluble liquids orsuspension concentrates; and during mixing of a product with water in aspray tank to reduce the wetting time of wettable powders and to improvethe penetration of water into water-dispersible granules. Examples ofwetting agents used in wettable powder, suspension concentrate, andwater-dispersible granule formulations are: sodium lauryl sulphate;sodium dioctyl sulfosuccinate; alkyl phenol ethoxylates; and aliphaticalcohol ethoxylates.

A dispersing agent is a substance which adsorbs onto the surface of aparticles and helps to preserve the state of dispersion of the particlesand prevents them from reaggregating. Dispersing agents are added toagrochemical formulations to facilitate dispersion and suspension duringmanufacture, and to ensure the particles redisperse into water in aspray tank. They are widely used in wettable powders, suspensionconcentrates and water-dispersible granules. Surfactants that are usedas dispersing agents have the ability to adsorb strongly onto a particlesurface and provide a charged or steric barrier to reaggregation ofparticles. The most commonly used surfactants are anionic, non-ionic, ormixtures of the two types. For wettable powder formulations, the mostcommon dispersing agents are sodium lignosulfonates. For suspensionconcentrates, very good adsorption and stabilization are obtained usingpolyelectrolytes, such as sodium naphthalene sulfonate formaldehydecondensates. Tristyrylphenol ethoxylate phosphate esters are also used.Non-ionics such as alkylarylethylene oxide condensates and EO-PO blockcopolymers are sometimes combined with anionics as dispersing agents forsuspension concentrates. In recent years, new types of very highmolecular weight polymeric surfactants have been developed as dispersingagents. These have very long hydrophobic ‘backbones’ and a large numberof ethylene oxide chains forming the ‘teeth’ of a ‘comb’ surfactant.These high molecular weight polymers can give very good long-termstability to suspension concentrates because the hydrophobic backboneshave many anchoring points onto the particle surfaces. Examples ofdispersing agents used in agrochemical formulations are: sodiumlignosulfonates; sodium naphthalene sulfonate formaldehyde condensates;tristyrylphenol ethoxylate phosphate esters; aliphatic alcoholethoxylates; alkyl ethoxylates; EO-PO block copolymers; and graftcopolymers.

An emulsifying agent is a substance which stabilizes a suspension ofdroplets of one liquid phase in another liquid phase. Without theemulsifying agent the two liquids would separate into two immiscibleliquid phases. The most commonly used emulsifier blends containalkylphenol or aliphatic alcohol with twelve or more ethylene oxideunits and the oil-soluble calcium salt of dodecylbenzenesulfonic acid. Arange of hydrophile-lipophile balance (“HLB”) values from 8 to 18 willnormally provide good stable emulsions. Emulsion stability can sometimesbe improved by the addition of a small amount of an EO-PO blockcopolymer surfactant.

A solubilizing agent is a surfactant which will form micelles in waterat concentrations above the critical micelle concentration. The micellesare then able to dissolve or solubilize water-insoluble materials insidethe hydrophobic part of the micelle. The type of surfactants usuallyused for solubilization are non-ionics: sorbitan monooleates; sorbitanmonooleate ethoxylates; and methyl oleate esters.

Surfactants are sometimes used, either alone or with other additivessuch as mineral or vegetable oils as adjuvants to spray-tank mixes toimprove the biological performance of the pesticide on the target. Thetypes of surfactants used for bioenhancement depend generally on thenature and mode of action of the pesticide. However, they are oftennon-ionics such as: alkyl ethoxylates; linear aliphatic alcoholethoxylates; aliphatic amine ethoxylates.

A carrier or diluent in an agricultural formulation is a material addedto the pesticide to give a product of the required strength. Carriersare usually materials with high absorptive capacities, while diluentsare usually materials with low absorptive capacities. Carriers anddiluents are used in the formulation of dusts, wettable powders,granules and water-dispersible granules.

Organic solvents are used mainly in the formulation of emulsifiableconcentrates, ULV (ultra low volume) formulations, and to a lesserextent granular formulations. Sometimes mixtures of solvents are used.The first main groups of solvents are aliphatic paraffinic oils such askerosene or refined paraffins. The second main group and the most commoncomprises the aromatic solvents such as xylene and higher molecularweight fractions of C9 and C10 aromatic solvents. Chlorinatedhydrocarbons are useful as cosolvents to prevent crystallization ofpesticides when the formulation is emulsified into water. Alcohols aresometimes used as cosolvents to increase solvent power.

Thickeners or gelling agents are used mainly in the formulation ofsuspension concentrates, emulsions and suspoemulsions to modify therheology or flow properties of the liquid and to prevent separation andsettling of the dispersed particles or droplets. Thickening, gelling,and anti-settling agents generally fall into two categories, namelywater-insoluble particulates and water-soluble polymers. It is possibleto produce suspension concentrate formulations using clays and silicas.Examples of these types of materials, include, but are limited to,montmorillonite, e.g. bentonite; magnesium aluminum silicate; andattapulgite. Water-soluble polysaccharides have been used asthickening-gelling agents for many years. The types of polysaccharidesmost commonly used are natural extracts of seeds and seaweeds or aresynthetic derivatives of cellulose. Examples of these types of materialsinclude, but are not limited to, guar gum; locust bean gum; carrageenam;alginates; methyl cellulose; sodium carboxymethyl cellulose (SCMC);hydroxyethyl cellulose (HEC). Other types of anti-settling agents arebased on modified starches, polyacrylates, polyvinyl alcohol andpolyethylene oxide. Another good anti-settling agent is xanthan gum.

Microorganisms cause spoilage of formulated products. Thereforepreservation agents are used to eliminate or reduce their effect.Examples of such agents include, but are not limited to: propionic acidand its sodium salt; sorbic acid and its sodium or potassium salts;benzoic acid and its sodium salt; p-hydroxybenzoic acid sodium salt;methyl p-hydroxybenzoate; and 1,2-benzisothiazalin-3-one (BIT).

The presence of surfactants, which lower interfacial tension, oftencauses water-based formulations to foam during mixing operations inproduction and in application through a spray tank. In order to reducethe tendency to foam, anti-foam agents are often added either during theproduction stage or before filling into bottles. Generally, there aretwo types of anti-foam agents, namely silicones and non-silicones.Silicones are usually aqueous emulsions of dimethyl polysiloxane whilethe non-silicone anti-foam agents are water-insoluble oils, such asoctanol and nonanol, or silica. In both cases, the function of theanti-foam agent is to displace the surfactant from the air-waterinterface.

For further information, see “CHEMISTRY AND TECHNOLOGY OF AGROCHEMICALFORMULATIONS” edited by D. A. Knowles, copyright 1998 by Kluwer AcademicPublishers. Also see “INSECTICIDES IN AGRICULTURE ANDENVIRONMENT—RETROSPECTS AND PROSPECTS” by A. S. Perry, I. Yamamoto, I.Ishaaya, and R. Perry, copyright 1998 by Springer-Verlag.

Applications

The actual amount of pesticide to be applied to loci of pests isgenerally not critical and can readily be determined by those skilled inthe art. In general, concentrations from about 0.01 grams of pesticideper hectare to about 5000 grams of pesticide per hectare are expected toprovide good control.

The locus to which a pesticide is applied can be any locus inhabited byan pest, for example, vegetable crops, fruit and nut trees, grape vines,ornamental plants, domesticated animals, the interior or exteriorsurfaces of buildings, and the soil around buildings. Controlling pestsgenerally means that pest populations, activity, or both, are reduced ina locus. This can come about when: pest populations are repulsed from alocus; when pests are incapacitated in or around a locus; or pests areexterminated, in whole or in part, in or around a locus. Of course acombination of these results can occur. Generally, pest populations,activity, or both are desirably reduced more than fifty percent,preferably more than 90 percent.

Generally, with baits, the baits are placed in the ground where, forexample, termites can come into contact with the bait. Baits can also beapplied to a surface of a building, (horizontal, vertical, or slant,surface) where, for example, ants, termites, cockroaches, and flies, cancome into contact with the bait.

Because of the unique ability of the eggs of some pests to resistpesticides repeated applications may be desirable to control newlyemerged larvae.

Systemic movement of pesticides in plants may be utilized to controlpests on one portion of the plant by applying the pesticides to adifferent portion of the plant. For example, control of foliar-feedinginsects can be controlled by drip irrigation or furrow application, orby treating the seed before planting. Seed treatment can be applied toall types of seeds, including those from which plants geneticallytransformed to express specialized traits will germinate. Representativeexamples include those expressing proteins toxic to invertebrate pests,such as Bacillus thuringiensis or other insecticidal toxins, thoseexpressing herbicide resistance, such as “Roundup Ready” seed, or thosewith “stacked” foreign genes expressing insecticidal toxins, herbicideresistance, nutrition-enhancement or any other beneficial traits.Furthermore, such seed treatments with the invention disclosed in thisdocument can further enhance the ability of a plant to better withstandstressful growing conditions. This results in a healthier, more vigorousplant, which can lead to higher yields at harvest time.

It should be readily apparent that the invention can be used with plantsgenetically transformed to express specialized traits, such as Bacillusthuringiensis or other insecticidal toxins, or those expressingherbicide resistance, or those with “stacked” foreign genes expressinginsecticidal toxins, herbicide resistance, nutrition-enhancement or anyother beneficial traits.

The invention disclosed in this document is suitable for controllingendoparasites and ectoparasites in the veterinary medicine sector or inthe field of animal keeping. Compounds are applied in a known manner,such as by oral administration in the form of, for example, tablets,capsules, drinks, granules, by dermal application in the form of, forexample, dipping, spraying, pouring on, spotting on, and dusting, and byparenteral administration in the form of, for example, an injection.

The invention disclosed in this document can also be employedadvantageously in livestock keeping, for example, cattle, sheep, pigs,chickens, and geese. Suitable formulations are administered orally tothe animals with the drinking water or feed. The dosages andformulations that are suitable depend on the species.

Before a pesticide can be used or sold commercially, such pesticideundergoes lengthy evaluation processes by various governmentalauthorities (local, regional, state, national, international).Voluminous data requirements are specified by regulatory authorities andmust be addressed through data generation and submission by the productregistrant or by another on the product registrant's behalf. Thesegovernmental authorities then review such data and if a determination ofsafety is concluded, provide the potential user or seller with productregistration approval. Thereafter, in that locality where the productregistration is granted and supported, such user or seller may use orsell such pesticide.

The headings in this document are for convenience only and must not beused to interpret any portion thereof.

TABLE 1 # Structure  2

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129

mp ¹H NMR # IR (cm⁻¹) MS (° C.) (CDCl₃, δ)¹  2 551.1 (M − H) 108-1248.55 (s, 1H), 8.15 (d, J = 8.7 Hz, 2H), 7.80 (d, J = 9.0 Hz, 2H), 7.55(d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.7 Hz, 2H), 6.90 (s, 1H), 5.17 (dd, J= 9.5, 3.4 Hz, 1H), 4.73 (d, J = 1.9 Hz, 1H), 3.79-3.62 (m, 2H), 3.51(s, 3H), 3.49 (s, 3H), 3.39 (s, 3H), 3.28 (t, J = 9.4 Hz, 1H), 1.35 (d,J = 6.3 Hz, 3H)  4 459 (M − H) 151-155 8.54 (s, 1H), 8.14 (d, J = 8.5Hz, 2H), 7.79 (d, J = 8.9 Hz, 2H), 7.55-7.48 (m, 2H), 7.37 (d, J = 8.5Hz, 2H), 6.77-6.73 (m, 1H), 2.18-1.06 (m, 10H), 1.00-0.93 (m, 3H)  5 449(M − H) 136-138 8.53 (s, 1H), 8.12 (d, J = 7.9 Hz, 2H), 7.79 (d, J = 9.0Hz, 2H), 7.46 (d, J = 8.9 Hz, 2H), 7.37 (d, J = 9.1 Hz, 2H), 6.70 (s,1H), 3.59 (s, 2H), 3.42 (s, 3H), 1.54 (s, 6H)  6 447 (M − H) 161-1648.53 (s, 1H), 8.12 (d, J = 8.7 Hz, 2H), 7.78 (d, J = 9.2 Hz, 2H), 7.47(d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.9 Hz, 2H), 6.61 (s, 1H), 1.84-1.77(m, 2H), 1.51 (s, 6H), 1.46-1.32 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H)  73334, 1758, 590 (M + H), 8.60 (s, 1H), 8.16 (s, 1H), 8.05 (d, J = 9.1Hz, 1740, 1725, 588 (M − H)⁻ 2H), 7.77 (d, J = 9.1 Hz, 2H), 7.57 (d, J =9.0 1616, 1517 Hz, 2H), 7.35 (d, J = 8.9 Hz, 2H), 5.81 (s, 1H), 4.37 (q,J = 7.1 Hz, 2H), 1.43 (s, 6H), 1.37 (t, J = 7.1 Hz, 3H)  8 473 (M − H)170-173 8.54 (s, 1H), 8.15 (d, J = 8.5 Hz, 2H), 7.79 (d, J = 9.1 Hz,2H), 7.48 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.9 Hz, 2H), 6.80 (br, 1H),1.78 (s, 6H)  10 457 (M + H) 203-207 8.55 (s, 1H), 8.14 (d, J = 8.7 Hz,2H), 7.80 (d, J = 9.0 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 7.39 (d, J =8.9 Hz, 2H), 6.65 (s, 1H), 5.17-4.92 (m, 1H), 1.32 (d, J = 6.3 Hz, 6H) 17 479 (M + H) 88-90 8.55 (s, 1H), 8.13 (d, J = 8.7 Hz, 2H), 7.79 (d, J= 9.0 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 6.87(s, 1H), 5.41-5.21 (m, 1H), 4.16 (qd, J = 7.1, 1.2 Hz, 2H), 2.71 (dd, J= 15.4, 7.5 Hz, 1H), 2.57 (dd, J = 15.4, 5.6 Hz, 1H), 1.39 (d, J = 6.3Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H)  18 495 (M + H), 72-75 8.54 (s, 1H),8.12 (d, J = 8.7 Hz, 2H), 7.79 (d, 493 (M − H) J = 8.9 Hz, 2H), 7.48 (d,J = 8.7 Hz, 2H), 7.38 (d, J = 8.6 Hz, 2H), 6.79 (s, 1H), 3.69 (dd, J =5.5, 3.9 Hz, 2H), 3.68 (s, 2H), 3.56 (dd, J = 5.8, 3.5 Hz, 2H), 3.37 (s,3H), 1.54 (s, 6H)  19 433 (M + H), 163-165 8.53 (s, 1H), 8.10 (d, J =8.6 Hz, 2H), 7.77 (d, J = 431 (M − H) 8.9 Hz, 2H), 7.48 (d, J = 8.5 Hz,2H), 7.36 (d, J = 8.6 Hz, 2H), 6.77 (s, 1H), 6.18 (dd, J = 17.5, 10.9Hz, 1H), 5.23 (d, J = 17.5 Hz, 1H), 5.13 (d, J = 10.9 Hz, 1H), 1.59 (s,6H)  20 479 (M + H), 151-154 8.54 (s, 1H), 8.12 (d, J = 8.5 Hz, 2H),7.78 (d, J = 477 (M − H) 8.9 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 7.37 (d,J = 8.6 Hz, 2H), 6.89 (s, 1H), 4.25 (q, J = 7.2 Hz, 2H), 1.64 (s, 6H),1.28 (t, J = 7.1 Hz, 3H)  21 483 (M + H) 174-177 8.52 (s, 1H), 8.09 (d,J = 8.8 Hz, 2H), 7.77 (d, J = 9.0 Hz, 2H), 7.54-7.32 (m, 8H), 7.31-7.18(m, 1H), 6.82 (s, 1H), 1.85 (s, 6H)  22 513 (M + H), 131-133 8.54 (s,1H), 8.13 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 511 (M − H) 9.2 Hz, 2H),7.49 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.7 Hz,2H), 6.84 (d, J = 8.7 Hz, 2H), 6.73 (s, 1H), 5.17-5.04 (m, 1H), 3.78 (s,3H), 2.96 (dd, J = 13.8, 6.3 Hz, 1H), 2.77 (dd, J = 13.8, 6.7 Hz, 1H),1.28 (d, J = 6.3 Hz, 3H)  25 421 (M + H), 177-179 8.54 (s, 1H), 8.11 (d,J = 8.7 Hz, 2H), 7.78 (d, J = 419 (M − H) 9.0 Hz, 2H), 7.48 (d, J = 8.7Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 6.64 (s, 1H), 1.53 (s, 9H)  28HRMS-FAB (m/z) 164.5-167.0 8.78 (d, J = 2.0 Hz, 1H), 8.63 (s, 1H), 8.14(d, J = [M + H]⁺ calcd for 8.8 Hz, 2H), 7.91 (m, 3H), 7.80 (d, J = 8.6Hz, C₂₄H₁₇F₆N₅O₂, 2H), 7.71-7.66 (m, 1H), 7.49 (d, J = 8.7 Hz, 2H),521.129; found, 6.96 (s, 1H), 5.99 (q, J = 6.7 Hz, 1H), 1.66 (d, J =521.1286 6.7 Hz, 3H)  29 HRMS-FAB (m/z) 177.5-179.5 8.64 (s, 1H), 8.16(d, J = 8.7 Hz, 2H), [M + H]⁺ calcd for 7.90 (d, J = 8.5 Hz, 2H), 7.79(d, J = 8.6 Hz, 2H), C₂₆H₁₆F₆N₄O₂, 7.75-7.64 (m, 4H), 7.51 (d, J = 8.7Hz, 2H), 530.118; found, 6.93 (s, 1H), 6.56 (d, J = 2.3 Hz, 1H), 2.77530.1175 (d, J = 2.3 Hz, 1H)  30 HRMS-FAB (m/z) 152-154 8.69 (s, 1H),8.13 (d, J = 8.7 Hz, 2H), 7.90 (d, J = [M + H]⁺ calcd for 8.5 Hz, 2H),7.78 (d, J = 8.6 Hz, 2H), 7.50 (d, C₂₅H₂₁F₃N₄O₂, J = 8.7 Hz, 2H),7.41-7.34 (m, 4H), 7.33-7.27 466.162; found, (m, 1H), 6.86 (s, 1H), 5.68(t, J = 6.9 Hz, 1H), 466.1619 2.01 (dq, J = 22.1, 7.4 Hz, 1H), 1.95-1.82(m, 1H), 0.95 (t, J = 7.4 Hz, 3H)  31 HRMS-FAB (m/z) 170-173 8.63 (s,1H), 8.15 (d, J = 8.7 Hz, 2H), 7.89 (d, J = [M + H]⁺ calcd for 8.5 Hz,2H), 7.78 (d, J = 8.6 Hz, 2H), 7.60 C₂₅H₁₇F₃N₄O₂, (dd, J = 7.7, 1.8 Hz,2H), 7.51 (d, J = 8.6 Hz, 462.130; found, 2H), 7.45-7.32 (m, 3H), 6.90(s, 1H), 6.52 (d, J = 462.1305 2.2 Hz, 1H), 2.73 (d, J = 2.3 Hz, 1H)  32HRMS-FAB (m/z) 181-184 8.55 (s, 1H), 8.13 (d, J = 8.7 Hz, 2H), 7.80 (d,J = [M + H]⁺ calcd for 9.0 Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H), 7.38 (d,C₂₁H₁₈ClF₅N₄O₃, J = 8.9 Hz, 2H), 6.75 (s, 1H), 3.89 (s, 2H), 1.61504.0988; found, (s, 6H) 504.1002  33 588 ([M + H]⁺), 173-175 8.78 (d, J= 1.9 Hz, 1H), 8.55 (s, 1H), 8.14 (d, J = 586 ([M − H]⁻) 8.8 Hz, 2H),7.89 (dd, J = 8.1, 2.1 Hz, 1H), 7.79 (d, J = 9.1 Hz, 2H), 7.74-7.65 (m,1H), 7.48 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 9.0 Hz, 2H), 6.89 (s, 1H),5.99 (q, J = 6.7 Hz, 1H), 1.66 (d, J = 6.7 Hz, 3H)  34 (thin film)HRMS-FAB (m/z) 8.89 (s, 1H), 8.14 (d, J = 8.7 Hz, 2H), 7.85 (d, J =3230, 3114, [M + H]⁺ calcd for 9.0 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H),7.38 3063, 2974, C₂₆H₂₁F₅N₄O₃, (dd, J = 9.6, 6.7 Hz, 6H), 7.33-7.26 (m,1H), 2941, 1719, 532.153; found, 6.89 (s, 1H), 5.68 (t, J = 6.9 Hz, 1H),2.08-1.94 1615, 1516, 532.1539 (m, 1H), 1.94-1.81 (m, 1H), 0.94 (t, J =7.4 Hz, 1445, 1416, 3H) 1315, 1225, 1137, 1092, 1051, 985, 843  35HRMS-FAB (m/z)   139-142.5 8.54 (s, 1H), 8.12 (d, J = 8.7 Hz, 2H), 7.78(d, J = [M + H]⁺ calcd for 9.0 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.48(d, C₂₄H₁₈F₃IN₄O₃, J = 8.6 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.15594.0376; found, (d, J = 8.3 Hz, 2H), 6.79 (s, 1H), 5.84 (q, J = 6.6594.0411 Hz, 1H), 1.59 (d, J = 6.7 Hz, 3H)  36 HRMS-FAB (m/z)157.5-159   8.53 (s, 1H), 8.19 (d, J = 8.5 Hz, 1H), 8.12 (app [M + H]⁺calcd for d, J = 8.7 Hz, 3H), 7.81 (d, J = 8.1 Hz, 1H), 7.78C₂₇H₂₀F₃N₅O₃, (d, J = 9.0 Hz, 2H), 7.72 (ddd, J = 8.4, 6.9, 1.4519.1518; found, Hz, 1H), 7.58-7.47 (m, 4H), 7.37 (d, J = 8.3 Hz,519.1527 2H), 7.01 (s, 1H), 6.12 (q, J = 6.7 Hz, 1H), 1.76 (d, J = 6.7Hz, 3H)  37 HRMS-FAB (m/z) 152.5-155   8.54 (s, 1H), 8.11 (d, J = 8.8Hz, 2H), 7.78 (d, J = [M + H]⁺ calcd for 9.1 Hz, 2H), 7.57 (t, J = 7.7Hz, 1H), 7.50 (d, C₂₄H₂₁F₃N₅O₃, J = 8.8 Hz, 2H), 7.37 (dd, J = 9.0, 0.7Hz, 2H), 484.1591; found, 7.17 (d, J = 7.7 Hz, 1H), 7.07 (d, J = 7.7 Hz,484.1589 1H), 6.99 (s, 1H), 5.91 (q, J = 6.7 Hz, 1H), 2.57 (s, 3H), 1.65(d, J = 6.7 Hz, 3H)  38 HRMS-FAB (m/z) 149-151 8.52 (s, 1H), 8.12 (d, J= 8.8 Hz, 2H), 7.78 (d, J = [M + H] calcd for 9.1 Hz, 2H), 7.49 (d, J =8.7 Hz, 2H), 7.40- C₂₇H₂₅F₃N₄O₃, 7.35 (m, 2H), 7.33 (d, J = 8.2 Hz, 2H),7.23 (d, J = 510.1879; found, 8.1 Hz, 2H), 6.76 (s, 1H), 5.91 (q, J =6.6 Hz, 510.1889 1H), 2.97-2.85 (m, 1H), 1.62 (d, J = 6.6 Hz, 3H), 1.25(d, J = 6.9 Hz, 6H)  39 (thin film) HRMS-FAB (m/z) 8.53 (s, 1H), 8.13(d, J = 8.8 Hz, 2H), 7.78 (d, J = 3317, 1723, [M + H]⁺ calcd for 9.1 Hz,2H), 7.53-7.42 (m, 4H), 7.38 (dd, J = 1518, 1263, C₂₄H₁₈BrF₃N₄O₃, 9.0,0.7 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 6.76 1224, 1071 546.0514; found,(s, 1H), 5.87 (q, J = 6.6 Hz, 1H), 1.60 (d, J = 6.6 546.0513 Hz, 3H)  40HRMS-FAB (m/z)   189-190.5 8.53 (s, 1H), 8.12 (d, J = 8.8 Hz, 2H), 7.78(d, J = [M + H]⁺ calcd for 9.1 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 7.43-C₂₈H₂₇F₃N₄O₃, 7.31 (m, 6H), 6.79 (s, 1H), 5.92 (q, J = 6.6 Hz, 524.2035;found, 1H), 1.62 (d, J = 6.6 Hz, 3H), 1.32 (s, 9H) 524.2058  41 HRMS-FAB(m/z) 154-156 8.78 (d, J = 1.8 Hz, 1H), 8.54 (s, 1H), 8.13 (d, J = [M +H]⁺ calcd for 8.7 Hz, 2H), 7.89 (dd, J = 8.1, 2.0 Hz, 1H), C₂₄H₁₇F₆N₅O₃,7.78 (d, J = 9.0 Hz, 2H), 7.69 (d, J = 8.1 Hz, 537.124; found, 1H), 7.48(d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.4 537.1235 Hz, 2H), 6.94 (s, 1H),5.99 (q, J = 6.6 Hz, 1H), 1.66 (d, J = 6.7 Hz, 3H)  42 HRMS-FAB (m/z)128-131 (400 MHz, DMSO-d₆) 10.11 (s, 1H), 9.36 (s, [M + H]⁺ calcd for1H), 8.05 (d, J = 9.1 Hz, 2H), 8.01 (d, J = 8.7 C₂₅H₁₈F₆N₄O₃, Hz, 2H),7.77 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 536.128; found, 8.2 Hz, 2H), 7.60(d, J = 8.6 Hz, 4H), 5.90 (q, J = 536.1284 6.5 Hz, 1H), 1.57 (d, J = 6.6Hz, 3H)  43 (thin film) HRMS-FAB (m/z) 8.54 (s, 1H), 8.14 (d, J = 8.8Hz, 2H), 7.78 (d, J = 3318, 1734, [M + H]⁺ calcd for 9.1 Hz, 2H), 7.63(d, J = 8.2 Hz, 2H), 7.55- 1519, 1327, C₃₀H₂₀F₆N₄O₃, 7.47 (m, 4H),7.42-7.30 (m, 7H), 6.95 (s, 1H), 1265, 1220 598.144; found, 6.94 (s, 1H)598.1445  44 493 ([M + H]⁺),   132-134.5 8.53 (s, 1H), 8.13 (d, J = 8.8Hz, 2H), 7.78 (d, J = 491 ([M − H]⁻), 9.0 Hz, 2H), 7.53-7.43 (m, 4H),7.41-7.32 (m, 4H), 6.78 (s, 1H), 5.90 (q, J = 6.6 Hz, 1H), 3.07 (s, 1H),1.60 (d, J = 6.6 Hz, 3H)  45 494 ([M + H]⁺), 186.5-187.5 8.54 (s, 1H),8.14 (d, J = 8.7 Hz, 2H), 7.78 (d, J = 492 ([M − H]⁻) 9.0 Hz, 2H), 7.67(d, J = 8.4 Hz, 2H), 7.55- 7.43 (m, 4H), 7.38 (dd, J = 8.9, 0.6 Hz, 2H),6.81 (s, 1H), 5.92 (q, J = 6.6 Hz, 1H), 1.61 (d, J = 6.7 Hz, 3H)  46 470([M + H]⁺), 143-145 8.61 (ddd, J = 4.8, 1.6, 0.8 Hz, 1H), 8.54 (s, 1H),468 ([M − H]⁻) 8.11 (d, J = 8.7 Hz, 2H), 7.78 (d, J = 9.1 Hz, 2H), 7.69(td, J = 7.7, 1.8 Hz, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.41-7.32 (m, 3H),7.22 (ddd, J = 7.5, 4.9, 1.1 Hz, 1H), 7.08 (s, 1H), 5.95 (q, J = 6.6 Hz,1H), 1.66 (d, J = 6.7 Hz, 3H)  47 484 ([M + H]⁺), 55-75 8.93 (d, J = 1.6Hz, 1H), 8.55 (s, 1H), 8.14 (d, J = 482 ([M − H]⁻) 8.8 Hz, 2H), 8.07(dd, J = 8.2, 2.0 Hz, 1H), 7.79 (d, J = 9.0 Hz, 2H), 7.50 (app t, J =8.9 Hz, 3H), 7.42-7.34 (m, 2H), 7.06 (s, 1H), 5.98 (q, J = 6.6 Hz, 1H),2.80 (s, 3H), 1.67 (d, J = 6.7 Hz, 3H)  48 (thin film) 470 ([M + H]⁺),(400 MHz, CD₃OD) 9.03 (s, 1H), 8.51 (dd, J = 3243, 1731, 468 ([M − H]⁻)4.6, 1.6 Hz, 2H), 8.02 (d, J = 8.9 Hz, 2H), 7.94 1607, 1548, (d, J = 9.1Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 1518, 1445, 7.45 (ddd, J = 9.6, 6.8,1.0 Hz, 4H), 5.86 (q, J = 1416, 1313, 6.6 Hz, 1H), 1.58 (d, J = 6.7 Hz,3H) 1228  49 HRMS-FAB (m/z) 168.5-171   8.51 (s, 1H), 8.10 (d, J = 8.8Hz, 2H), 7.76 (d, J = [M + H]⁺ calcd for 9.0 Hz, 2H), 7.60 (d, J = 8.3Hz, 2H), 7.52 (d, C₂₆H₂₀F₆N₄O₃, J = 8.3 Hz, 2H), 7.44 (d, J = 8.8 Hz,2H), 7.39- 550.144; found, 7.31 (m, 2H), 6.89 (s, 1H), 1.84 (s, 6H)550.146  50 HRMS-FAB (m/z) 166.5-168   8.53 (s, 1H), 8.15 (d, J = 8.8Hz, 2H), 7.78 (d, J = [M + H]⁺ calcd for 9.1 Hz, 2H), 7.64 (d, J = 8.1Hz, 2H), 7.57- C₂₄H₁₆F₆N₄O₃, 7.45 (m, 4H), 7.37 (dd, J = 9.0, 0.8 Hz,2H), 522.1127; found, 6.92 (s, 1H), 5.27 (s, 2H) 522.1139  51 HRMS-FAB(m/z)   199-202.5 (300 MHz, DMSO-d₆) 10.16 (s, 1H), 9.36 (s, [M + H]⁺calcd for 1H), 8.59 (s, 1H), 8.10-7.95 (m, 5H), 7.68-7.50 C₂₄H₁₇F₆N₅O₄,(m, 5H), 5.86 (q, J = 6.5 Hz, 1H), 1.58 (d, J = 553.1185; found, 6.6 Hz,3H) 553.1191  52 HRMS-FAB (m/z) 156.5-158   (300 MHz, acetone-d₆) 9.18(s, 1H), 9.13 (s, [M + H]⁺ calcd for 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.16(d, J = 8.8 C₂₄H₁₅ClF₃N₅O₃, Hz, 2H), 8.13-8.06 (m, 3H), 7.71 (d, J = 8.7Hz, 513.0816; found, 2H), 7.63-7.52 (m, 3H), 6.63 (d, J = 2.3 Hz, 1H),513.0832 3.46 (d, J = 2.3 Hz, 1H)  53 HRMS-FAB (m/z) 177-179 (300 MHz,acetone-d₆) 9.24 (s, 1H), 9.13 (s, [M + H]⁺ calcd for 1H), 9.02 (d, J =1.9 Hz, 1H), 8.33 (dd, J = 8.1, C₂₅H₁₅ClF₆N₅O₃, 2.1 Hz, 1H), 8.16 (d, J= 8.8 Hz, 2H), 8.10 (d, J = 547.1079; found, 9.1 Hz, 2H), 7.97 (d, J =8.2 Hz, 1H), 7.72 (d, 547.1098 J = 8.8 Hz, 2H), 7.63-7.52 (m, 2H), 6.74(d, J = 2.3 Hz, 1H), 3.51 (d, J = 2.3 Hz, 1H)  54 (thin film) HRMS-FAB(m/z) 8.54 (s, 1H), 8.14 (d, J = 8.7 Hz, 2H), 7.78 (d, J = 3248, 3111,[M + H]⁺ calcd for 9.0 Hz, 2H), 7.55 (s, 1H), 7.49 (d, J = 8.6 Hz, 3062,1728, C₂₁H₁₅ClF₃N₅O₃S, 2H), 7.38 (d, J = 8.8 Hz, 2H), 6.83 (s, 1H), 6.091608, 1518, 509.054; found, (q, J = 6.6 Hz, 1H), 1.71 (d, J = 6.6 Hz,3H) 1445, 1417, 509.0531 1262, 1223, 1053  55 (thin film) HRMS-FAB (m/z)8.53 (s, 1H), 8.22 (d, J = 2.4 Hz, 1H), 8.12 (d, J = 3307, 3119, [M +H]⁺ calcd for 8.7 Hz, 2H), 7.78 (d, J = 9.0 Hz, 2H), 7.63 2986, 2950,C₂₄H₂₀F₃N₅O₄, (dd, J = 8.6, 2.5 Hz, 1H), 7.48 (d, J = 8.7 Hz, 1725,1611, 499.147; found, 2H), 7.42-7.32 (m, 2H), 6.81 (s, 1H), 6.75 (d, J =1517, 1495, 499.1463 8.6 Hz, 1H), 5.89 (q, J = 6.6 Hz, 1H), 3.93 (s,1445, 1416, 3H), 1.61 (d, J = 6.6 Hz, 3H) 1257, 1215  56 (thin film)HRMS-FAB (m/z) 8.54 (s, 1H), 8.45 (d, J = 2.5 Hz, 1H), 8.13 (d, J =3259, 3117, [M + H]⁺ calcd for 8.8 Hz, 2H), 7.78 (d, J = 9.1 Hz, 2H),7.68 3062, 2986, C₂₃H₁₇ClF₃N₅O₃, (dd, J = 8.3, 2.5 Hz, 1H), 7.48 (d, J =8.5 Hz, 1729, 1597, 503.097; found, 2H), 7.37 (dd, J = 8.9, 0.6 Hz, 2H),7.33 (d, J = 1518, 1445, 503.0970 8.3 Hz, 1H), 6.97 (s, 1H), 5.91 (q, J= 6.6 Hz, 1417, 1263, 1H), 1.62 (d, J = 6.7 Hz, 3H) 1225  57 539 ([M +H]⁺), 185-187 8.94 (s, 2H), 8.55 (s, 1H), 8.15 (d, J = 8.8 Hz, 537 ([M −H]⁻) 2H), 7.78 (d, J = 9.0 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 7.36 (d, J= 0.7 Hz, 2H), 6.91 (s, 1H), 6.01 (q, J = 6.7 Hz, 1H), 1.71 (d, J = 6.8Hz, 3H)  58 (thin film) HRMS-FAB (m/z) 8.54 (s, 1H), 8.11 (d, J = 8.7Hz, 2H), 7.78 (d, J = 3295, 3120, [M + H]⁺ calcd for 9.0 Hz, 2H), 7.49(d, J = 8.8 Hz, 2H), 7.44- 3066, 3036, C₂₅H₂₁F₃N₄O₄, 7.31 (m, 7H), 6.97(s, 1H), 5.99 (dd, J = 8.0, 3.6 2934, 2894, 498.152; found, Hz, 1H),3.80 (dd, J = 10.9, 8.0 Hz, 1H), 3.63 1728, 1597, 498.1511 (dd, J =10.9, 3.7 Hz, 1H), 3.43 (s, 3H) 1518, 1493, 1445, 1263, 1223  59HRMS-FAB (m/z) 136-138 8.53 (s, 1H), 8.12 (d, J = 8.7 Hz, 2H), 7.78 (d,J = [M + H]⁺ calcd for 9.0 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H), 7.45-C₂₄H₁₉F₃N₄O₃, 7.34 (m, 6H), 7.34-7.28 (m, 1H), 6.82 (s, 1H), 468.140;found, 5.92 (q, J = 6.6 Hz, 1H), 1.62 (d, J = 6.6 Hz, 468.141 3H)  60469 ([M + H]⁺) 122.5-125.0 8.54 (s, 1H), 8.12 (d, J = 8.7 Hz, 2H), 7.78(d, J = 9.0 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 7.46- 7.34 (m, 6H),7.34-7.28 (m, 1H), 6.78 (s, 1H), 5.92 (q, J = 6.6 Hz, 1H), 1.63 (d, J =6.6 Hz, 3H)  61 469 ([M + H]⁺) 123.5-125.0 8.53 (s, 1H), 8.12 (d, J =8.7 Hz, 2H), 7.78 (d, J = 9.0 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 7.44-7.34 (m, 6H), 7.34-7.28 (m, 1H), 6.81 (s, 1H), 5.92 (q, J = 6.6 Hz, 1H),1.62 (d, J = 6.6 Hz, 3H)  62 (thin film) 562 ([M + H]⁺) 8.53 (s, 1H),8.12 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 3320, 3120, 9.2 Hz, 2H),7.58-7.40 (m, 4H), 7.37 (dd, J = 2973, 2938, 9.0, 0.8 Hz, 2H), 7.28-7.14(m, 2H), 6.85 (s, 1722, 1596, 1H), 5.62 (t, J = 6.9 Hz, 1H), 2.11-1.73(m, 2H), 1518, 1490, 0.93 (t, J = 7.4 Hz, 3H) 1445, 1416, 1314, 1263,1222, 1051, 732  63 (thin film) HRMS-FAB (m/z) 8.54 (s, 1H), 8.12 (d, J= 8.8 Hz, 2H), 7.78 (d, J = 3318, 3121, [M + H]⁺ calcd for 9.0 Hz, 2H),7.54-7.47 (m, 3H), 7.43 (ddd, J = 3064, 2973, C₂₅H₂₀BrF₃N₄O₃, 7.7, 1.9,1.4 Hz, 1H), 7.37 (dd, J = 9.0, 0.8 Hz, 2938, 1720, 560.067; found 2H),7.29 (dt, J = 7.9, 1.5 Hz, 1H), 7.22 (t, J = 1596, 1518, 560.0672 7.7Hz, 1H), 6.90 (s, 1H), 5.62 (t, J = 6.8 Hz, 1491, 1445, 1H), 2.08-1.74(m, 2H), 0.94 (t, J = 7.4 Hz, 3H) 1416, 1313, 1263, 1222, 1051, 909, 732 64 HRMS-FAB (m/z) 110-113 8.54 (s, 1H), 8.13 (d, J = 8.8 Hz, 2H), 7.78(d, J = [M + H]⁺ calcd for 9.0 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 7.43(d, C₂₅H₁₈F₆N₄O₄, J = 8.6 Hz, 2H), 7.38 (dd, J = 9.0, 0.8 Hz, 2H),552.123; found, 7.22 (dd, J = 8.7, 0.8 Hz, 2H), 6.81 (s, 1H), 5.91552.1230 (q, J = 6.6 Hz, 1H), 1.61 (d, J = 6.6 Hz, 3H)  65 (thin film)HRMS-FAB (m/z) 8.54 (s, 1H), 8.13 (d, J = 8.8 Hz, 2H), 7.78 (d, J =3229, 3181, [M + H]⁺ calcd for 9.0 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H),7.40- 3108, 3048, C₂₅H₂₀ClF₃N₄O₃, 7.34 (m, 3H), 7.31-7.19 (m, 3H), 6.86(s, 1H), 1742, 1600, 516.118; found, 5.64 (t, J = 6.9 Hz, 1H), 2.08-1.74(m, 2H), 0.94 1541, 1519, 516.1174 (t, J = 7.4 Hz, 3H) 1441, 1417, 1310,1248, 1222, 1083, 985, 843  66 (thin film) HRMS-FAB (m/z) 8.55 (s, 1H),8.15 (d, J = 8.8 Hz, 2H), 7.83-7.75 3250, 3117, [M + H]⁺ calcd for (m,2H) 7.75-7.64 (m, 4H), 7.51 (d, J = 8.7 Hz, 3061, 2126, C₂₆H₁₆F₆N₄O₃,2H), 7.43-7.34 (m, 2H), 6.90 (s, 1H), 6.56 (d, J = 1735, 1610, 546.113;found, 2.2 Hz, 1H), 2.76 (d, J = 2.4 Hz, 1H) 1549, 1519, 546.1125 1492,1445, 1417, 1328, 1263, 1220, 1068, 1050, 848  67 HRMS-FAB (m/z)161.5-163.0 8.54 (s, 1H), 8.13 (d, J = 8.7 Hz, 2H), 7.78 (d, J = [M +H]⁺ calcd for 9.0 Hz, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.49 (d,C₂₆H₂₀F₆N₄O₃, J = 8.5 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 7.43- 550.144;found, 7.27 (m, 2H), 6.85 (s, 1H), 5.71 (t, J = 6.8 Hz, 550.1440 1H),2.11-1.73 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H)  68 HRMS-FAB (m/z)  118-119.5 8.54 (s, 1H), 8.13 (d, J = 8.7 Hz, 2H), 7.78 (d, J = [M +H]⁺ calcd for 9.0 Hz, 2H), 7.67 (s, 1H), 7.63-7.55 (m, 2H),C₂₅H₁₈F₆N₄O₃, 7.54-7.46 (m, 3H), 7.38 (dd, J = 9.0, 0.7 Hz, 536.128;found, 2H), 6.85 (s, 1H), 5.96 (q, J = 6.6 Hz, 1H), 1.63 536.1282 (d, J= 6.6 Hz, 3H)  69 HRMS-FAB (m/z) 171.5-173.5 8.53 (s, 1H), 8.11 (d, J =8.8 Hz, 2H), 7.78 (d, J = [M + H]⁺ calcd for 9.1 Hz, 2H), 7.67 (app t, J= 7.0 Hz, 2H), 7.58 C₂₅H₁₈F₆N₄O₃, (dd, J = 11.3, 3.9 Hz, 1H), 7.49 (d, J= 8.7 Hz, 536.128; found, 2H), 7.44-7.32 (m, 3H), 6.85 (s, 1H), 6.27 (q,J = 536.1282 6.5 Hz, 1H), 1.61 (d, J = 6.5 Hz, 3H)  70 HRMS-FAB (m/z)118-121 8.54 (s, 1H), 8.13 (d, J = 8.7 Hz, 2H), 7.78 (d, J = [M + H]⁺calcd for 9.0 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 7.46- C₂₅H₁₉F₃N₄O₃,7.30 (m, 7H), 6.89 (s, 1H), 6.29 (d, J = 5.9 Hz, 480.141; found, 1H),6.09 (ddd, J = 17.0, 10.4, 5.9 Hz, 1H), 5.38 480.1411 (dt, J = 17.2, 1.3Hz, 1H), 5.31 (dt, J = 10.5, 1.2 Hz, 1H)  71 HRMS-FAB (m/z) 146.5-148.58.53 (s, 1H), 8.11 (d, J = 8.7 Hz, 2H), 7.78 (d, J = [M + H]⁺ calcd for9.0 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 7.41- C₂₇H₂₅F₃N₄O₃, 7.33 (m, 6H),7.32-7.27 (m, 1H), 6.83 (s, 1H), 510.188; found, 5.74 (dd, J = 7.5, 6.5Hz, 1H), 2.09-1.91 (m, 510.1884 1H), 1.91-1.71 (m, 1H), 1.59-1.02 (m,4H), 0.89 (t, J = 7.0 Hz, 3H)  72 (thin film) HRMS-FAB (m/z) 8.53 (s,1H), 8.13 (d, J = 8.7 Hz, 2H), 7.77 (d, J = 3317, 3123, [M + H]⁺ calcdfor 9.0 Hz, 2H), 7.58 (dd, J = 7.9, 1.6 Hz, 2H), 3066, 3036,C₂₆H₁₉F₃N₄O₃, 7.50 (d, J = 8.6 Hz, 2H), 7.44-7.32 (m, 5H), 6.91 2246,1731, 492.141; found, (s, 1H), 6.49 (q, J = 2.1 Hz, 1H), 1.93 (d, J =2.2 1598, 1518, 492.1413 Hz, 3H) 1492, 1445, 1416, 1263, 1217, 1039,986, 909, 850, 732  73 HRMS-FAB (m/z) 196-198 8.69 (s, 1H), 8.11 (d, J =8.7 Hz, 2H), 7.80 (d, J = [M + H]⁺ calcd for 9.0 Hz, 2H), 7.51 (d, J =8.7 Hz, 2H), 7.37 (d, C₂₄H₁₇Cl₂F₃N₄O₃, J = 8.6 Hz, 2H), 7.30 (d, J = 8.0Hz, 2H), 7.14 536.063; found, (dd, J = 8.4, 7.7 Hz, 1H), 6.90 (s, 1H),6.56 (q, J = 536.0634 6.9 Hz, 1H), 1.73 (d, J = 6.9 Hz, 3H)  74 (thinfilm) HRMS-FAB (m/z) 8.98 (s, 1H), 8.08 (d, J = 8.1 Hz, 2H), 7.86-7.743251, 3111, [M + H]⁺ calcd for (m, 2H), 7.44 (d, J = 7.8 Hz, 2H),7.36-7.26 (m, 3064, 2962, C₂₆H₂₃F₃N₄O₃, 6H), 7.26-7.20 (m, 1H), 6.80 (s,1H), 5.69 (dd, J = 2874, 1724, 496.172; found, 7.4, 6.5 Hz, 1H),1.96-1.83 (m, 1H), 1.80-1.66 1607, 1518, 496.1727 (m, 1H), 1.46-1.19 (m,2H), 0.88 (t, J = 7.4 Hz, 1493, 1445, 3H) 1416, 1313, 1262, 1225, 1179,1107, 1058  75 HRMS-FAB (m/z) 131-135 8.56 (s, 1H), 8.14 (d, J = 8.7 Hz,2H), 7.95 (d, J = [M + H]⁺ calcd for 8.4 Hz, 2H), 7.79 (d, J = 9.0 Hz,2H), 7.60 (d, C₂₅H₂₁F₃N₄O₅S, J = 8.4 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H),7.38 546.118; found, (d, J = 8.4 Hz, 2H), 6.87 (s, 1H), 5.95 (q, J = 6.6546.1187 Hz, 1H), 3.05 (s, 3H), 1.63 (d, J = 6.7 Hz, 3H)  76 HRMS-FAB(m/z) 158-160 (400 MHz, DMSO-d₆) 10.00 (s, 1H), 9.37 (s, [M + H]⁺ calcdfor 1H), 8.06 (d, J = 9.0 Hz, 2H), 8.01 (d, J = 8.7 C₂₂H₁₇F₃N₄O₃S, Hz,2H), 7.67-7.56 (m, 4H), 7.53 (dd, J = 5.1, 474.097; found, 1.2 Hz, 1H),7.19 (d, J = 3.4 Hz, 1H), 7.03 (dd, J = 474.0976 5.1, 3.5 Hz, 1H), 6.11(q, J = 6.5 Hz, 1H), 1.66 (d, J = 6.6 Hz, 3H)  77 HRMS-FAB (m/z) 135-137(400 MHz, DMSO-d₆) 9.96 (s, 1H), 9.36 (s, 1H), [M + H]⁺ calcd for 8.05(d, J = 9.0 Hz, 2H), 8.01 (d, J = 8.7 Hz, C₂₂H₁₇F₃N₄O₃S, 2H), 7.62 (d, J= 8.6 Hz, 2H), 7.60 (d, J = 8.6 474.097; found, Hz, 2H), 7.57-7.51 (m,2H), 7.20 (dd, J = 4.8, 474.0979 1.5 Hz, 1H), 5.93 (q, J = 6.5 Hz, 1H),1.59 (d, J = 6.6 Hz, 3H)  78 (thin film) HRMS-FAB (m/z) 8.93 (s, 1H),8.14 (d, J = 8.7 Hz, 2H), 7.84 (d, J = 3251, 3064, [M + H]⁺ calcd for9.0 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 7.44- 2960, 1724, C₂₇H₂₅F₃N₄O₃,7.32 (m, 6H), 7.30 (ddd, J = 6.7, 3.8, 1.7 Hz, 1608, 1518, 510.1883;found, 1H), 6.86 (s, 1H), 5.83 (dd, J = 8.6, 5.3 Hz, 1H), 1493, 1445,510.187 2.03-1.80 (m, 1H), 1.75-1.52 (m, 2H), 0.98 (d, J = 1416, 1313,6.3 Hz, 3H), 0.97 (d, J = 6.2 Hz, 3H) 1262, 1224, 1179, 1056, 849  79HRMS-FAB (m/z) 123-126 8.88 (s, 1H), 8.14 (d, J = 8.7 Hz, 2H), 7.83 (d,J = [M + H]⁺ calcd for 9.0 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 7.43-C₂₅H₂₀F₄N₄O₃, 7.30 (m, 4H), 7.04 (t, J = 8.7 Hz, 2H), 6.91 (s, 500.147;found, 1H), 5.64 (t, J = 7.0 Hz, 1H), 2.07-1.91 (m, 1H), 500.14751.91-1.75 (m, 1H), 0.92 (t, J = 7.4 Hz, 3H)  80 HRMS-FAB (m/z) 97-998.71 (s, 1H), 8.17 (d, J = 8.7 Hz, 2H), 7.81 (d, J = [M + H]⁺ calcd for9.0 Hz, 2H), 7.66 (s, 1H), 7.51 (d, J = 8.4 Hz, C₂₂H₁₄F₆N₄O₄, 2H), 7.46(t, J = 1.7 Hz, 1H), 7.39 (d, J = 8.5 512.092; found, Hz, 2H), 7.05 (s,1H), 6.55 (s, 1H), 6.22 (q, J = 512.0919 6.8 Hz, 1H)  81 HRMS-FAB (m/z)144-147 8.58 (s, 1H), 8.13 (d, J = 8.7 Hz, 2H), 7.79 (d, J = [M + H]⁺calcd for 9.0 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H), 7.38 (d,C₂₄H₁₈F₃N₄O₃Cl, J = 8.3 Hz, 2H), 7.34 (app s, 4H), 6.80 (s, 1H),502.102; found, 5.87 (q, J = 6.6 Hz, 1H), 1.59 (d, J = 6.6 Hz, 502.10203H)  82 HRMS-FAB (m/z) 142-144 (400 MHz, DMSO-d₆) 10.19 (s, 1H), 9.37(s, [M + H]⁺ calcd for 1H), 8.04 (dd, J = 10.4, 8.9 Hz, 4H), 7.68-7.56C₂₅H₁₇F₃N₄O₃, (m, 6H), 7.51-7.29 (m, 3H), 6.47 (d, J = 2.2 Hz, 478.125;found, 1H), 3.88 (d, J = 2.2 Hz, 1H) 478.1256  83 HRMS-FAB (m/z) 158-1608.99 (s, 1H), 8.18 (d, J = 8.7 Hz, 2H), 7.87 (d, J = [M + H]⁺ calcd for9.0 Hz, 2H), 7.56 (d, J = 8.7 Hz, 2H), 7.47- C₂₉H₂₁F₃N₄O₃, 7.30 (m,12H), 7.09 (s, 1H), 6.94 (s, 1H) 530.157; found, 530.1564  84 HRMS-FAB(m/z) 142-144 8.56 (s, 1H), 8.12 (d, J = 8.4 Hz, 2H), 7.78 (d, J = [M +H]⁺ calcd for 8.6 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 7.38 C₂₄H₁₈F₄N₄O₃,(dd, J = 8.6, 5.4 Hz, 4H), 7.05 (t, J = 8.7 Hz, 486.131; found, 2H),6.85 (s, 1H), 5.89 (q, J = 6.6 Hz, 1H), 1.60 486.1318 (d, J = 6.6 Hz,3H)  85 HRMS-FAB (m/z) 127-131 8.53 (s, 1H), 8.12 (d, J = 8.7 Hz, 2H),7.76 (d, J = [M + H]⁺ calcd for 9.0 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H),7.42- C₂₅H₂₁F₃N₄O₃, 7.15 (m, 7H), 6.97 (s, 1H), 5.68 (t, J = 6.9 Hz,482.156; found, 1H), 2.07-1.75 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H)482.1568  86 HRMS-FAB (m/z) 8.55 (s, 1H), 8.13 (d, J = 8.7 Hz, 2H), 7.79(d, J = [M + H]⁺ calcd for 9.0 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.38(d, C₂₃H₂₀F₃N₅O₄, J = 8.3 Hz, 2H), 6.91 (s, 1H), 5.82 (q, J = 6.8487.146; found, Hz, 1H), 2.46 (s, 3H), 2.36 (s, 3H), 1.60 (d, J =487.1468 6.9 Hz, 3H)  87 HRMS-FAB (m/z) 193-195 8.54 (s, 1H), 8.13 (d, J= 8.7 Hz, 2H), 7.79 (d, J = [M + H]⁺ calcd for 9.0 Hz, 2H), 7.50 (d, J =8.5 Hz, 2H), 7.37 (d, C₁₉H₁₇F₃N₄O₃, J = 8.5 Hz, 2H), 6.71 (s, 1H),5.23-4.88 (m, 1H), 406.125; found, 1.31 (d, J = 6.3 Hz, 6H) 406.1252  88HRMS-FAB (m/z) 8.54 (s, 1H), 8.12 (d, J = 8.8 Hz, 2H), 7.79 (d, J = [M +H]⁺ calcd for 9.1 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 7.46- C₂₆H₂₁F₃N₄O₃,7.28 (m, 7H), 6.82 (s, 1H), 5.21 (d, J = 8.9 Hz, 494.156; found, 1H),1.45-1.29 (m, 1H), 0.76-0.56 (m, 3H), 494.1567 0.51-0.38 (m, 1H)  89HRMS-FAB (m/z) 181-183 8.53 (s, 1H), 8.11 (d, J = 8.4 Hz, 2H), 7.78 (d,J = [M + H]⁺ calcd for 9.0 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), 7.37 (d,C₂₆H₂₃F₃N₄O₃, J = 8.5 Hz, 2H), 7.07 (dd, J = 8.5, 6.3 Hz, 1H), 496.172;found, 7.01 (d, J = 7.4 Hz, 2H), 6.79 (s, 1H), 6.34 (q, J = 496.1726 6.9Hz, 1H), 2.50 (s, 6H), 1.65 (d, J = 7.0 Hz, 3H)  90 HRMS-FAB (m/z) 8.55(s, 1H), 8.15 (d, J = 8.7 Hz, 2H), 7.78 (d, J = [M + H]⁺ calcd for 9.0Hz, 2H), 7.58-7.46 (m, 4H), 7.48-7.34 (m, C₂₄H₁₆F₆N₄O₃, 5H), 7.11 (s,1H), 6.17 (q, J = 6.9 Hz, 1H) 522.112; found, 522.1128  91 HRMS-FAB(m/z) 160-162 8.53 (s, 1H), 8.11 (d, J = 8.7 Hz, 2H), 7.77 (d, J = [M +H]⁺ calcd for 9.0 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H), 7.37 (d,C₂₅H₂₁F₃N₄O₃, J = 8.4 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 7.18 482.156;found, (d, J = 7.9 Hz, 2H), 6.84 (s, 1H), 5.89 (q, J = 6.6 482.156 Hz,1H), 2.34 (s, 3H), 1.61 (d, J = 6.6 Hz, 3H)  92 HRMS-FAB (m/z) 94-978.53 (s, 1H), 8.12 (d, J = 8.7 Hz, 2H), 7.78 (d, J = [M + H]⁺ calcd for9.0 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 7.37 (d, C₂₅H₂₁F₃N₄O₃, J = 8.4Hz, 2H), 7.30-7.17 (m, 3H), 7.12 (d, J = 482.156; found, 7.5 Hz, 1H),6.86 (s, 1H), 5.88 (q, J = 6.6 Hz, 482.157 1H), 2.37 (s, 3H), 1.61 (d, J= 6.6 Hz, 3H)  93 HRMS-FAB (m/z) 147-149 8.53 (s, 1H), 8.12 (d, J = 8.7Hz, 2H), 7.77 (d, J = [M + H]⁺ calcd for 9.0 Hz, 2H), 7.49 (d, J = 8.6Hz, 2H), 7.45- C₂₅H₂₁F₃N₄O₃, 7.39 (m, 1H), 7.37 (d, J = 8.7 Hz, 2H),7.27-7.11 482.156; found, (m, 3H), 6.90 (s, 1H), 6.13 (q, J = 6.5 Hz,1H), 482.157 2.43 (s, 3H), 1.59 (d, J = 6.6 Hz, 3H)  94 525 ([M +H]⁺) >150 (3:2 mixture of diastereomers) 8.52 (s, 1H), 8.11 (d, J = 8.6Hz, 2H), 7.77 (d, J = 9.0 Hz, 2H), 7.59-7.43 (m, 2H), 7.37 (d, J = 8.4Hz, 2H), 6.98-6.89 (m, 2H), 6.82-6.63 (m, 2H), 6.39 (d, J = 2.2 Hz,0.6H), 6.25 (d, J = 3.0 Hz, 0.4H), 3.76-3.62 (m, 0.6H), 3.09 (dd, J =16.4, 5.9 Hz, 0.4H), 2.67 (d, J = 9.0 Hz, 1.2H), 2.33-2.20 (m, 0.8H),2.27 (s, 3H), 1.14 (d, J = 6.8 Hz, 1.5H), 1.08 (d, J = 7.1 Hz, 1.5H)  95HRMS-FAB (m/z) 171-173 8.54 (s, 1H), 8.13 (d, J = 8.7 Hz, 2H), 7.79 (d,J = [M + H]⁺ calcd for 9.2 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 7.38C₂₅H₁₉F₃N₄O₄, (dd, J = 9.1, 0.8 Hz, 2H), 7.13 (dd, J = 15.8, 7.8496.135; found, Hz, 2H), 6.94 (ddd, J = 9.7, 7.6, 1.7 Hz, 2H), 496.1366.76 (s, 1H), 6.62 (t, J = 2.5 Hz, 1H), 3.03 (ddd, J = 17.4, 12.3, 5.9Hz, 1H), 2.77 (ddd, J = 17.0, 6.2, 3.1 Hz, 1H), 2.33-1.98 (m, 2H)  96HRMS-FAB (m/z) 158-159 8.53 (s, 1H), 8.11 (d, J = 8.7 Hz, 2H), 7.78 (d,J = [M + H]⁺ calcd for 9.0 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 7.36 (d,C₂₃H₂₁F₃N₄O₃, J = 8.4 Hz, 2H), 6.77 (s, 1H), 2.23 (q, J = 7.5 458.156;found, Hz, 2H), 1.73 (s, 6H), 1.13 (t, J = 7.5 Hz, 3H) 458.157  97 (thinfilm) HRMS-FAB (m/z) 8.53 (s, 1H), 8.11 (d, J = 8.7 Hz, 2H), 7.78 (d, J= 3317, 3122, [M + H]⁺ calcd for 8.9 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H),7.37 (d, 2981, 2933, C₂₅H₂₁F₃N₄O₄, J = 8.9 Hz, 2H), 7.35 (d, J = 8.8 Hz,2H), 6.90 2839, 1724, 498.151; found, (d, J = 8.7 Hz, 2H), 6.79 (s, 1H),5.88 (q, J = 6.6 1615, 1518, 498.151 Hz, 1H), 3.80 (s, 3H), 1.61 (d, J =6.6 Hz, 3H) 1492, 1445, 1416, 1249, 1225, 1179, 1111, 1064, 986, 847  98HRMS-FAB (m/z) 182-184 8.55 (s, 1H), 8.12 (d, J = 8.7 Hz, 2H), 7.78 (d,J = [M + H]⁺ calcd for 9.0 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 7.37 (d,C₁₈H₁₅F₃N₄O₃, J = 8.5 Hz, 2H), 6.81 (s, 1H), 4.25 (q, J = 7.1 392.109;found, Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H) 392.109  99 HRMS-FAB (m/z)130-133 (300 MHz, CDCl₃-CD₃OD) 8.60 (s, 1H), 7.97 [M + H]⁺ calcd for (d,J = 8 Hz, 2H), 7.75 (d, J = 8 Hz, 2H), 7.44 C₂₄H₂₄F₃N₅O₃, (d, J = 8 Hz,2H), 7.30 (d, J = 8 Hz, 2H), 3.83 487.183; found, (br, 1H), 3.21 (s,2H), 2.22 (s, 6H), 1.65 (s, 6H) 487.183 100 HRMS-FAB (m/z) 173-176 8.53(s, 1H), 8.13 (d, J = 8.7 Hz, 2H), 7.77 (d, J = [M + H]⁺ calcd for 9.0Hz, 2H), 7.50 (d, J = 8.2 Hz, 2H), 7.37 (d, C₂₇H₂₅F₃N₄O₄, J = 8.4 Hz,2H), 7.14 (d, J = 8.6 Hz, 2H), 6.83 526.182; found, (d, J = 8.7 Hz, 2H),6.77 (s, 1H), 3.78 (s, 3H), 526.183 3.12 (s, 2H), 1.50 (s, 6H) 101HRMS-FAB (m/z) 111-115 8.54 (s, 1H), 8.13 (d, J = 8.7 Hz, 2H), 7.78 (d,J = [M + H]⁺ calcd for 9.1 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H), 7.37 (d,C₂₄H₂₇F₃N₄O₃, J = 8.3 Hz, 2H), 6.79 (s, 1H), 4.86-4.76 (m, 1H), 476.203;found, 1.71-1.50 (m, 4H), 1.47-1.16 (m 6H), 0.94 (t, J = 476.204 7.4 Hz,3H), 0.88 (t, J = 6.7 Hz, 3H) 102 HRMS-FAB (m/z) 123-124 8.54 (s, 1H),8.13 (d, J = 8.7 Hz, 2H), 7.78 (d, J = [M + H]⁺ calcd for 9.0 Hz, 2H),7.51 (d, J = 8.5 Hz, 2H), 7.37 (d, C₂₄H₂₇F₃N₄O₃, J = 8.5 Hz, 2H), 6.76(s, 1H), 5.07-4.81 (m, 1H), 476.203; found, 1.96-1.58 (m, 1H), 1.58-1.47(m, 1H), 1.47-1.17 476.204 (m, 8H), 1.29 (d, J = 6.2 Hz, 3H), 0.88 (t, J= 6.7 Hz, 3H) 103 HRMS-FAB (m/z) 165-166 8.54 (s, 1H), 8.13 (d, J = 8.7Hz, 2H), 7.78 (d, J = [M + H]⁺ calcd for 9.0 Hz, 2H), 7.52 (d, J = 8.4Hz, 2H), 7.37 (d, C₂₂H₂₃F₃N₄O₃, J = 8.6 Hz, 2H), 6.77 (s, 1H), 4.71 (q,J = 6.4 448.172; found, Hz, 1H), 1.22 (d, J = 6.4 Hz, 3H), 0.95 (s, 9H)448.172 104 HRMS-FAB (m/z) 171-173 8.54 (s, 1H), 8.13 (d, J = 8.7 Hz,2H), 7.78 (d, J = [M + H]⁺ calcd for 9.0 Hz, 2H), 7.50 (d, J = 8.5 Hz,2H), 7.37 (d, C₁₇H₁₃F₃N₄O₃, J = 8.4 Hz, 2H), 6.85 (s, 1H), 3.80 (s, 3H)378.093; found, 378.094 105 HRMS-FAB (m/z) 155-157 8.54 (s, 1H), 8.13(d, J = 8.7 Hz, 2H), 7.78 (d, J = [M + H]⁺ calcd for 9.0 Hz, 2H), 7.51(d, J = 8.5 Hz, 2H), 7.46- C₂₃H₁₇F₃N₄O₃, 7.32 (m, 7H), 6.89 (s, 1H),5.22 (s, 2H) 454.125; found, 454.125 106 HRMS-FAB (m/z) 196-197 8.52 (s,1H), 8.11 (d, J = 8.6 Hz, 2H), 7.77 (d, J = [M + H]⁺ calcd for 8.9 Hz,2H), 7.47 (d, J = 8.2 Hz, 2H), 7.37 (d, C₂₂H₁₉F₃N₄O₃, J = 8.7 Hz, 2H),7.30-7.24 (m, 2H), 7.24-7.16 480.140; found, (m, 2H), 6.78 (s, 1H),5.63-5.58 (m, 1H), 3.35 480.141 (dd, J = 17.0, 6.1 Hz, 2H), 3.11 (dd, J= 17.0, 2.3 Hz, 2H) 107 HRMS-FAB (m/z) 143-145 8.54 (s, 1H), 8.13 (d, J= 8.7 Hz, 2H), 7.78 (d, J = [M + H]⁺ calcd for 9.0 Hz, 2H), 7.48 (d, J =8.4 Hz, 2H), 7.37 (d, C₂₅H₂₁F₃N₄O₃, J = 8.4 Hz, 2H), 7.34-7.27 (m, 2H),7.27- 482.156; found, 7.19 (m, 3H), 6.76 (s, 1H), 5.16 (h, J = 6.3 Hz,482.1567 1H), 3.02 (dd, J = 13.7, 6.4 Hz, 1H), 2.83 (dd, J = 13.7, 6.7Hz, 1H), 1.30 (d, J = 6.3 Hz, 3H) 108 HRMS-FAB (m/z) 197-201 8.54 (s,1H), 8.12 (d, J = 8.7 Hz, 2H), 7.79 (d, J = [M + H]⁺ calcd for 9.0 Hz,2H), 7.47 (d, J = 8.2 Hz, 2H), 7.38 (d, C₂₆H₂₁F₃N₄O₃, J = 8.3 Hz, 2H),7.23-7.11 (m, 4H), 6.68 (s, 494.156; found, 1H), 3.51 (d, J = 16.5 Hz,2H), 3.20 (d, J = 16.5 494.157 Hz, 2H), 1.78 (s, 3H) 109 HRMS-FAB (m/z)187-190 8.54 (s, 1H), 8.14 (d, J = 8.7 Hz, 2H), 7.78 (d, J = [M + H]⁺calcd for 9.0 Hz, 2H), 7.51 (d, J = 7.0 Hz, 3H), 7.38 (d, C₂₅H₁₉F₃N₄O₃,J = 8.4 Hz, 2H), 7.35-7.21 (m, 3H), 6.77 (s, 1H), 480.140; found 6.26(dd, J = 6.9, 3.5 Hz, 1H), 3.19-3.10 (m, 480.1415 1H), 2.92 (ddd, J =16.1, 8.6, 4.6 Hz, 1H), 2.62- 2.49 (m, 1H), 2.21 (dddd, J = 14.0, 8.3,4.5, 3.7 Hz, 1H) 110 HRMS-FAB (m/z) 147-150 8.70 (s, 1H), 8.58 (d, J =4.1 Hz, 1H), 8.54 (s, [M + H]⁺ calcd for 1H), 8.13 (d, J = 8.7 Hz, 2H),7.78 (d, J = 9.0 C₂₃H₁₈F₃N₅O₃, Hz, 2H), 7.73 (dt, J = 7.9, 1.7 Hz, 1H),7.50 (d, J = 469.136; found, 8.6 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 7.32469.1366 (dd, J = 7.8, 4.9 Hz, 1H), 7.11 (s, 1H), 5.95 (q, J = 6.6 Hz,1H), 1.65 (d, J = 6.7 Hz, 3H) 111 HRMS-FAB (m/z) 171-173 8.54 (s, 1H),8.13 (d, J = 8.7 Hz, 2H), 7.78 (d, J = [M + H]⁺ calcd for 9.0 Hz, 2H),7.51 (d, J = 8.4 Hz, 2H), 7.43- C₂₃H₁₅F₃N₄O₃Cl₂, 7.32 (m, 4H), 7.24 (dd,J = 8.7, 7.3 Hz, 1H), 522.047; found, 6.92 (s, 1H), 5.51 (s, 2H)522.0480 112 HRMS-FAB (m/z) 134-136 8.56 (s, 1H), 8.16 (d, J = 8.6 Hz,2H), 7.78 (d, J = [M + H]⁺ calcd for 9.0 Hz, 2H), 7.58 (dd, J = 6.8, 2.9Hz, 2H), C₂₄H₁₆F₃N₅O₃, 7.55-7.43 (m, 5H), 7.38 (d, J = 8.4 Hz, 2H), 7.08479.120; found, (s, 1H), 6.53 (s, 1H) 479.1206 113 HRMS-FAB (m/z)161-162 9.05 (s, 1H), 8.17 (d, J = 8.7 Hz, 2H), 7.87 (d, J = [M + H]⁺calcd for 8.9 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.39 (d, C₂₁H₂₁F₃N₄O₃,J = 8.5 Hz, 2H), 6.80 (s, 1H), 4.80-4.71 (m, 1H), 434.156; found,1.72-1.53 (m, 4H), 0.95 (t, J = 7.4 Hz, 6H) 434.1568 114 HRMS-FAB (m/z)185-188 8.54 (s, 1H), 8.13 (d, J = 8.8 Hz, 2H), 7.79 (d, J = [M + H]⁺calcd for 9.0 Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H), 7.38 C₂₄H₁₄F₃N₄O₃, (dd,J = 9.0, 0.8 Hz, 2H), 6.84 (s, 1H), 6.18 (q, J = 558.094; found, 6.7 Hz,1H), 1.72 (d, J = 6.9 Hz, 3H) 558.0937 115 HRMS-FAB (m/z) 212.5-214.510.20 (s, 1H), 9.35 (s, 1H), 8.20 (d, J = 8.3 Hz, [M + H]⁺ calcd for1H), 8.10-7.95 (m, 6H), 7.58 (app t, J = 9.2 Hz, C₂₆H₁₇F₉N₄O₃, 4H), 6.09(q, J = 6.4 Hz, 1H), 1.59 (d, J = 6.5 604.116; found, Hz, 3H) 604.1154116 HRMS-FAB (m/z) 174.5-177.5 8.54 (s, 1H), 8.13 (d, J = 8.7 Hz, 2H),7.79 (d, J = [M + H]⁺ calcd for 9.0 Hz, 2H), 7.64-7.55 (m, 4H),7.54-7.31 (m, C₃₀H₂₃F₃N₄O₃, 9H), 6.81 (s, 1H), 5.97 (q, J = 6.5 Hz, 1H),1.67 544.1722; found, (d, J = 6.6 Hz, 3H) 544.1722 117 488 ([M + H]⁺),153.5-156   8.54 (s, 1H), 8.46 (t, J = 1.6 Hz, 1H), 8.12 (d, J = 486 ([M− H]⁻) 8.8 Hz, 2H), 7.78 (d, J = 9.0 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H),7.44-7.33 (m, 4H), 6.93 (s, 1H), 5.95 (q, J = 6.6 Hz, 1H), 1.66 (d, J =6.7 Hz, 3H) 118 504 ([M + H]⁺),   181-184.5 8.57 (dd, J = 2.4, 0.5 Hz,1H), 8.54 (s, 1H), 8.13 502 ([M − H]⁻) (d, J = 8.8 Hz, 2H), 7.79 (d, J =9.0 Hz, 2H), 7.68 (dd, J = 8.4, 2.5 Hz, 1H), 7.49 (d, J = 8.7 Hz, 2H),7.38 (dd, J = 9.1, 0.8 Hz, 2H), 7.37- 7.33 (m, 1H), 6.90 (s, 1H), 5.93(q, J = 6.6 Hz, 1H), 1.65 (d, J = 6.7 Hz, 3H) 119 500 ([M + H]⁺),143-148 8.54 (s, 1H), 8.34-8.28 (m, 1H), 8.11 (d, J = 8.8 498 ([M − H]⁻)Hz, 2H), 7.78 (d, J = 9.1 Hz, 2H), 7.48 (d, J = 8.8 Hz, 2H), 7.42-7.34(m, 2H), 7.32 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 8.6, 2.9 Hz, 1H), 6.94(s, 1H), 5.93 (q, J = 6.6 Hz, 1H), 3.85 (s, 3H), 1.66 (d, J = 6.7 Hz,3H) 120 (thin film) 504 ([M + H]⁺), 8.54 (s, 1H), 8.13 (d, J = 8.8 Hz,2H), 7.79 (d, J = 3301, 3119, 502 ([M − H]⁻) 9.1 Hz, 2H), 7.66 (t, J =7.8 Hz, 1H), 7.50 (d, 3061, 2987, J = 8.8 Hz, 2H), 7.41-7.35 (m, 2H),7.32 (d, J = 1721, 1596, 7.5 Hz, 1H), 7.28-7.24 (m, 1H), 6.92 (s, 1H),1517, 1491, 5.90 (q, J = 6.7 Hz, 1H), 1.66 (d, J = 6.7 Hz, 1439, 1311,3H) 1220, 1163, 1078, 985, 914, 846, 756, 732 121 HRMS-FAB (m/z) 172-1738.54 (s, 1H), 8.14 (d, J = 8.7 Hz, 2H), 7.79 (d, J = [M + H]⁺ calcd for9.0 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 7.38 C₂₇H₂₅F₃N₄O₃, (dd, J = 9.0,0.7 Hz, 2H), 6.87 (s, 2H), 6.77 (s, 510.188; found, 1H), 4.31-4.19 (m,2H), 3.10-2.97 (m, 2H), 2.37 510.1876. (s, 6H), 2.26 (s, 3H) 122HRMS-FAB (m/z) 186-188 (400 MHz, DMSO-d₆) 10.49 (s, 1H), 9.37 (s, [M +H]⁺ calcd for 1H), 8.08 (d, J = 3.4 Hz, 2H), 8.05 (d, J = 3.7C₂₂H₁₅F₃N₄O₃, Hz, 2H), 7.67 (d, J = 8.7 Hz, 2H), 7.61 (d, J = 440.109;found, 8.7 Hz, 2H), 7.45 (t, J = 7.9 Hz, 2H), 7.32-7.19 440.110 (m, 3H)123 HRMS-FAB (m/z) 219-221 (300 MHz, DMSO-d₆) 10.59 (s, 1H), 9.38 (d, J= [M + H]⁺ calcd for 0.4 Hz, 1H), 8.39 (d, J = 2.7 Hz, 1H), 8.09 (d,C₂₂H₁₆F₃N₅O₃, J = 2.6 Hz, 2H), 8.06 (d, J = 2.9 Hz, 2H), 7.69- 455.121;found, 7.59 (m, 4H), 7.34 (d, J = 8.7 Hz, 1H), 7.07-7.00 455.1206 (m,1H), 2.49 (s, 3H) 124 509 ([M + H]⁺) 153-168 8.56 (s, 1H), 8.19 (d, J =8.8 Hz, 2H), 7.80 (d, J = 9.1 Hz, 2H), 7.70 (d, J = 8.9 Hz, 1H), 7.63(d, J = 8.1 Hz, 1H), 7.59 (d, J = 8.9 Hz, 2H), 7.45- 7.35 (m, 4H), 7.21(s, 1H) 125 509 ([M + H]⁺) 161-169 8.56 (s, 1H), 8.19 (d, J = 8.8 Hz,2H), 7.80 (d, J = 9.1 Hz, 2H), 7.70 (d, J = 8.9 Hz, 1H), 7.61 (dd, J =18.0, 8.6 Hz, 3H), 7.40 (dd, J = 15.7, 7.7 Hz, 4H), 7.20 (s, 1H) 126 509([M + H]⁺) 183-188 8.56 (s, 1H), 8.19 (d, J = 8.7 Hz, 2H), 7.80 (d, J =9.0 Hz, 2H), 7.68 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 8.6 Hz, 2H), 7.37(dd, J = 15.2, 8.3 Hz, 4H), 7.13 (s, 1H) 127 459 ([M + H]⁺), 184-1888.56 (s, 1H), 8.18 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 457 ([M − H]⁻) 9.1Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 9.7 Hz, 2H), 7.29 (dd, J= 7.9, 1.5 Hz, 1H), 7.24-7.13 (m, 4H) 128 489 ([M + H]⁺)   179-182.58.56 (s, 1H), 8.18 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 9.1 Hz, 2H), 7.57(d, J = 8.5 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 2.4 Hz, 1H),7.22- 7.20 (m, 1H), 7.20-7.18 (m, 1H), 7.11 (br s, 1H), 7.09 (d, J = 8.5Hz, 1H), 2.26 (s, 3H) 129 517 ([M + H]⁺) 172-180 8.55 (s, 1H), 8.19 (d,J = 8.8 Hz, 2H), 7.80 (d, J = 9.1 Hz, 2H), 7.64-7.56 (m, 4H), 7.46 (qd,J = 7.7, 4.5 Hz, 5H), 7.37 (dd, J = 12.4, 7.8 Hz, 3H), 7.29 (d, J = 8.7Hz, 1H), 7.20 (dd, J = 9.0, 2.4 Hz, 1H), 7.13 (s, 1H) ¹All NMR datameasured in CDCl₃ at 300 or 400 MHz unless otherwise noted

TABLE 2 Compound % Mortality % Mortality % Mortality Number CEW 50μg/cm² BAW 50 μg/cm² GPA 200 ppm 1 A A B 2 B A B 3 B A B 4 B B B 5 A A B6 B A B 7 B B B 8 A A B 9 A A B 10 B A B 11 A A B 12 A A B 13 A A B 14 BB C 15 A A B 16 B B B 17 A B B 18 A A B 19 A A B 20 A A B 21 A A B 22 AA B 23 B B B 24 A A B 25 A A B 26 A A C 27 A A B 28 A A B 29 A A B 30 AA B 31 A A B 32 A A B 33 A A B 34 A A B 35 A A B 36 A A B 37 A A B 38 AA B 39 A A B 40 A A B 41 A A B 42 A A B 43 A A B 44 A A B 45 A A B 46 AA B 47 A A B 48 A A B 49 A A B 50 B B B 51 A A B 52 A A B 53 A A B 54 AA B 55 A A B 56 A A B 57 A A B 58 A A B 59 A A B 60 A A C 61 A A C 62 AA C 63 A A B 64 A A B 65 A A B 66 A A B 67 A A B 68 A A B 69 A A B 70 AA B 71 A A B 72 A A B 73 A A B 74 A A B 75 A A B 76 A A B 77 A A B 78 AA B 79 A A B 80 A A B 81 A A B 82 A A B 83 A A B 84 A A B 85 A A B 86 AA B 87 B A B 88 A A B 89 A A B 90 A A B 91 A A B 92 A A B 93 A A B 94 AA B 95 A A B 96 A A B 97 A A B 98 A A B 99 B B B 100 B B B 101 A A B 102B B B 103 B A B 104 A A B 105 A A B 106 A B B 107 A A B 108 B B B 109 AB B 110 A A B 111 A B B 112 A A B 113 A A B 114 B A B 115 B B B 116 A BB 117 A A B 118 A A B 119 A A B 120 A A B 121 A B B 122 A A B 123 B B B124 A A B 125 C C B 126 C C B 127 C C B 128 A A B 129 A A B 130 A A B131 A A B 132 B A B 133 A A B 134 B B B 135 A A B 136 B B B

1. A molecule of the following formula:

wherein: (a) Ar₁ is (1) furanyl, phenyl, pyridazinyl, pyridyl,pyrimidinyl, thienyl, or (2) substituted furanyl, substituted phenyl,substituted pyridazinyl, substituted pyridyl, substituted pyrimidinyl,or substituted thienyl, wherein said substituted furanyl, substitutedphenyl, substituted pyridazinyl, substituted pyridyl, substitutedpyrimidinyl, and substituted thienyl, have one or more substituentsindependently selected from H, F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy,C₃-C₆ halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl,C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl),OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)H, C(═O)NR_(x)R_(y),(C₁-C₆ alkyl)NR_(x)R_(y), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl),C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl),C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, phenoxy,substituted phenyl and substituted phenoxy wherein such substitutedphenyl and substituted phenoxy have one or more substituentsindependently selected from H, F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy,C₃-C₆ halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl,C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl),OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)H, C(═O)NR_(x)R_(y),(C₁-C₆ alkyl)NR_(x)R_(y), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl),C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl),C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆ alkyl)phenyl, and phenoxy; (b)Het is a 5 or 6 membered, saturated or unsaturated, heterocyclic ring,containing one or more heteroatoms independently selected from nitrogen,sulfur, or oxygen, and where Ar₁ and Ar₂ are not ortho to each other(but may be meta or para, such as, for a five membered ring they are 1,3and for a 6 membered ring they are either 1, 3 or 1,4), and where saidheterocyclic ring may also be substituted with one or more substituentsindependently selected from H, F, Cl, Br, I, CN, NO₂, oxo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, C₃-C₆cycloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,C₂-C₆ alkenyl, C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆haloalkyl), OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)H,C(═O)NR_(x)R_(y), (C₁-C₆ alkyl)NR_(x)R_(y), C(═O)(C₁-C₆ alkyl),C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl),C(═O)(C₃-C₆ cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl),C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, phenoxy,substituted phenyl and substituted phenoxy wherein such substitutedphenyl and substituted phenoxy have one or more substituentsindependently selected from H, F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy,C₃-C₆ halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl,C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl),OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)H, C(═O)NR_(x)R_(y),(C₁-C₆ alkyl)NR_(x)R_(y), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl),C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl),C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, and phenoxy; (c)Ar₂ is (1) furanyl, phenyl, pyridazinyl, pyridyl, pyrimidinyl, thienyl,or (2) substituted furanyl, substituted phenyl, substituted pyridazinyl,substituted pyridyl, substituted pyrimidinyl, or substituted thienyl,wherein said substituted furanyl, substituted phenyl, substitutedpyridazinyl, substituted pyridyl, substituted pyrimidinyl, andsubstituted thienyl, have one or more substituents independentlyselected from H, F, Cl, Br, I, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆alkynyl, S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)H, C(═O)NR_(x)R_(y), (C₁-C₆alkyl)NR_(x)R_(y), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆haloalkyl), C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆ cycloalkyl),C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl), C(═O)O(C₂-C₆ alkenyl),(C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆ alkyl), C(═O)(C₁-C₆alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, phenoxy, substituted phenyl andsubstituted phenoxy (wherein such substituted phenyl and substitutedphenoxy have one or more substituents independently selected from H, F,Cl, Br, I, CN, NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl,C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆alkyl), S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆haloalkyl), C(═O)H, C(═O)NR_(x)R_(y), (C₁-C₆ alkyl)NR_(x)R_(y),C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆ haloalkyl),C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆ cycloalkyl), C(═O)O(C₃-C₆cycloalkyl), C(═O)(C₁-C₆ haloalkyl), C(═O)(C₂-C₆ alkenyl), C(═O)O(C₂-C₆alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆ alkyl),C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, and phenoxy; (d) X₁ is Oor S; (e) X₂ is O or S; (f) R4 is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆cycloalkyl, C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆alkynyl, S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)H, C(═O)NR_(x)R_(y), (C₁-C₆alkyl)NR_(x)R_(y), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆haloalkyl), C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆ cycloalkyl),C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl), C(═O)O(C₂-C₆ alkenyl),(C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆ alkyl), C(═O)(C₁-C₆alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, phenoxy, wherein each alkyl,haloalkyl, cycloalkyl, halocycloalkyl, cycloalkoxy, halocycloalkoxy,alkoxy, haloalkoxy, alkenyl, alkynyl, phenyl, and phenoxy are optionallysubstituted with one or more substituents independently selected from F,Cl, Br, I, CN, NO₂, oxo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁C₃-C₆cycloalkyl, C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆alkynyl, S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl), OSO₂(C₁-C₆alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)H, C(═O)NR_(x)R_(y), (C₁-C₆alkyl)NR_(x)R_(y), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆haloalkyl), C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆ cycloalkyl),C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl), C(═O)O(C₂-C₆ alkenyl),(C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆ alkyl), C(═O)(C₁-C₆alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, and phenoxy; (j) n=0, I, or 2; (k)R_(x) and R_(y) are independently selected from H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, C₃-C₆ cycloalkoxy,C₃-C₆ halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl,C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆ haloalkyl),OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)H, C(═O)(C₁-C₆ alkyl),C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl),C(═O)(C₃-C₆ cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl),C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, and phenoxy; and(l) R1, R2, and R3 are independently selected from H, F, Cl, Br, I, CN,NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆halocycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C(═O)H, C(═O)NR_(x)R_(y),(C₁-C₆ alkyl)NR_(x)R_(y), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl),(C₁-C₆ alkyl)O(C₁-C₆ alkyl)O(C₁-C₆ alkyl), C(═O)(C₁-C₆ haloalkyl),C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆ cycloalkyl), C(═O)O(C₃-C₆cycloalkyl), C(═O)(C₂-C₆ alkenyl), C(═O)O(C₂-C₆ alkenyl), (C₁-C₆alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆ alkyl), C(═O)(C₁-C₆alkyl)C(═O)O(C₁-C₆ alkyl), C(═O)phenyl, phenyl, C₁-C₆ alkylphenyl,C(═O)phenoxy, phenoxy, C₁-C₆ alkylphenoxy, C(═O)Het-1, Het-1, or C₁-C₆alkylHet-1, wherein Het-1 is a 5- or 6-membered, saturated orunsaturated, heterocyclic ring, containing one or more heteroatomsindependently selected from nitrogen, sulfur or oxygen, and wherein eachalkyl, haloalkyl, cycloalkyl, halocycloalkyl, cycloalkoxy,halocycloalkoxy, alkoxy, haloalkoxy, alkenyl, alkynyl, phenyl, phenoxy,and Het-1, are optionally substituted with one or more substituentsindependently selected from F, Cl, Br, I, CN, NO₂, oxo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, C₃-C₆cycloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,C₂-C₆ alkenyl, C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆haloalkyl), OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)H,C(═O)NR_(x)R_(y), (C₁-C₆ alkyl)NR_(x)R_(y), (C₁-C₆ alkenyl)NR_(x)R_(y),(C₁-C₆ alkynyl)NR_(x)R_(y), C(═O)(C₁-C₆ alkyl), C(═O)O(C₁-C₆ alkyl),C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl), C(═O)(C₃-C₆cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl),C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, phenoxy, andHet-1, wherein R1 and R2 together can optionally form a 3- to12-membered saturated or unsaturated cyclic group which may contain oneor more heteroatoms selected from nitrogen, sulfur, and oxygen (with theproviso that there is preferably not a C₁—O— bond in such cyclic group)wherein said cyclic group may have one or more substituentsindependently selected from F, Cl, Br, I, CN, NO₂, oxo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, C₃-C₆cycloalkoxy, C₃-C₆ halocycloalkoxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,C₂-C₆ alkenyl, C₂-C₆ alkynyl, S(═O)_(n)(C₁-C₆ alkyl), S(═O)_(n)(C₁-C₆haloalkyl), OSO₂(C₁-C₆ alkyl), OSO₂(C₁-C₆ haloalkyl), C(═O)H,C(═O)NR_(x)R_(y), (C₁-C₆ alkyl)NR_(x)R_(y), C(═O)(C₁-C₆ alkyl),C(═O)O(C₁-C₆ alkyl), C(═O)(C₁-C₆ haloalkyl), C(═O)O(C₁-C₆ haloalkyl),C(═O)(C₃-C₆ cycloalkyl), C(═O)O(C₃-C₆ cycloalkyl), C(═O)(C₂-C₆ alkenyl),C(═O)O(C₂-C₆ alkenyl), (C₁-C₆ alkyl)O(C₁-C₆ alkyl), (C₁-C₆ alkyl)S(C₁-C₆alkyl), C(═O)(C₁-C₆ alkyl)C(═O)O(C₁-C₆ alkyl), phenyl, phenoxy, andHet-1.
 2. A molecule according to claim 1 wherein Ar₁ is a substitutedphenyl wherein said substituted phenyl, has one or more substituentsindependently selected from C₁-C₆ haloalkyl and C₁-C₆ haloalkoxy.
 3. Amolecule according to claim 1 wherein Het is a triazolyl.
 4. A moleculeaccording to claim 1 wherein Ar₂ is a phenyl.
 5. A molecule according toclaim 1 wherein R4 is an H or a C₁-C₆ alkyl.
 6. A molecule according toclaim 1 wherein R1, R2, and R3 are independently selected from H, CN,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C(═O)O(C₁-C₆ alkyl), phenyl, and Het-1
 7. A molecule accordingto claim 1 having one of the following structures


8. A process to apply a molecule according to claim 1 said processcomprising applying a molecule according to claim 1, to an area tocontrol a pest, in an amount sufficient to control such pest.
 9. Aprocess according to claim 8 wherein said pest is BAW, CEW, or GPA. 10.A molecule that is a pesticidally acceptable acid addition salt, a saltderivative, a solvate, or an ester derivative, of a molecule accordingto claim
 1. 11. A molecule according to claim 1 wherein at least one His ²H or at least one C is ¹⁴C.
 12. A composition comprising a moleculeaccording to claim 1 and at least one other compound havinginsecticidal, herbicidal, acaricidal, nematicidal, or fungicidalactivity.
 13. A composition comprising a molecule according to claim 1and a seed.
 14. A process comprising applying a molecule according toclaim 1 to a genetically modified plant, or genetically-modified seed,which has been genetically modified to express one or more specializedtraits.
 15. A process comprising: orally administering; or topicallyapplying; a molecule according to claim 1, to a non-human animal, tocontrol endoparasites, ectoparasites, or both.